Sjogren's Syndrome with Bronchiolar Involvement and Associated Granulomas
Thomas V. Colby, M.D. Mayo Clinic Scottsdale, Arizona
History Provided:
A 61-year-old woman underwent open lung biopsy.
Histologic Findings:
The basic architecture is intact. There is mild scarring in a central distribution along bronchioles. At
low power numerous lymphoid nodules are apparent. These are predominantly along bronchioles although
occasional follicles are present along interlobular septa. Rare germinal centers are present. The lymphoid
tissue contains numerous non-necrotizing granulomas. The lymphoid tissue shows a predilection for
bronchioles which show bronchiolitis, patchy mild chronic inflammation in the walls, muscle hypertrophy, and
peribronchiolar scarring and associated peribronchiolar metaplasia. For the most part the bronchiolar
lumens appear patent and there is minimal bronchiolar submucosal fibrosis. There is mural thickening of
pulmonary arteries, some of which also show endothelial thickening.
Scanning power microscopy shows preservation of lung architecture with scattered lymphoid follicles, some of which appear to be bronchiolocentric.
There is an inflammatory process centering on two bronchioles with lymphoid follicles, barely discernible granulomas, and bronchiolar scarring.
A non-necrotizing granuloma is identified within a lymphoid follicle.
This bronchiole shows focal chronic inflammation, smooth muscle hypertrophy, and peribronchiolar scarring and metaplasia.
Histologic Differential Diagnosis:
Given the variety of histologic findings above, one has a number of possibilities to consider. Ideally one
would like to explain all of the histologic findings with one diagnosis, but there is always the possibility
that a primary lesion has incited secondary changes (for example, airway injury associated with secondary
inflammation versus lymphoid proliferation associated with secondary airway injury).
The presence of inflammation along airways with associated granulomas, smooth muscle hypertrophy, mural
chronic inflammation, and peribronchiolar scarring, inflammation, and metaplasia all raise the possibility
of primary bronchiolar pathology. Broadly speaking (and forgetting the granulomas at the moment), one could
label this a chronic bronchiolitis with lymphoid follicles (follicular bronchiolitis), and the differential
would include: infection, changes distal to bronchiectasis, collagen vascular disease, inflammatory bowel
disease, chronic asthma, transplantation/GVH-associated, lymphoproliferative disease, diffuse
panbronchiolitis, immunoglobulin deficiencies, chronic aspiration, and idiopathic.
Peribronchiolar metaplasia as present in this case suggests healed bronchiolar injury. In addition to the
already mentioned conditions, one could add chronic extrinsic allergic alveolitis and healed bronchiolitis
of other causes.
Can one predict from the histology whether this patient will have obstructive, restrictive, or mixed
obstructive/restrictive disease? One might expect that bronchiolar pathology would be associated with
obstruction, but in this case the lumens are patent and there is peribronchiolar scarring that extends along
alveolar walls, and these changes are often associated with restrictive lung disease or mixed
restrictive/obstructive lung disease as well as radiologic infiltrates. This is an important point:
primary bronchiolar pathology may be associated with restrictive lung disease and radiologic infiltrative
disease.
The presence of granulomas should always first invoke the possibility of infection even though necrosis
is not present. In this case acid fast and fungal stains were negative, as were cultures. The differential
diagnosis of granulomas along bronchioles includes: infections, sarcoidosis, hypersensitivity pneumonitis,
collagen vascular diseases (especially Sjogren's syndrome), bronchocentric granulomatosis (BCG), Wegener's
granulomatosis (WG), aspiration, and pneumoconioses.
The absence of necrosis, foreign material, and character of the granulomas would tend to exclude BCG, WG,
aspiration, and pneumoconioses. The lack of coalescence of granulomas along lymphatic routes would be
against sarcoidosis. The relative prominence of the granulomas in this case and the lack of an alveolitis
diffusely involving alveolar walls would be against hypersensitivity pneumonitis. That would leave
infection and collagen vascular disease as primary possibilities based purely on the histology.
The lymphoid tissue raises the possibility ofa lymphoproliferative disorder. Lymphoid proliferations,
be they reactive or neoplastic, frequently have associated granulomas so the presence of granulomas would
not exclude the possibility of a lymphoproliferative disorder. Occasional granulomas may also accompany
diffuse lymphoid hyperplasia in the lung associated with HIV infection and other immunodeficiency syndromes.
Granulomas (sometimes even with necrosis) are not uncommonly associated with low-grade B-cell lymphomas
involving the lung.
The major histologic feature that serves to exclude lymphoma in this case is the lack of expansile sheets of
lymphoid cells. These are primary lymphoid follicles with occasional normal-appearing germinal center is
present. This case showed a mixed population of CD3 positive T cells and CD20 positive B cells comprising
the nodules. The B cells did not co-express CD43 and the overall immunoarchitecture was that of reactive
lymphoid tissue. Thus, based on the histology, a lymphoproliferative disorder is unlikely.
As a rule of thumb, histologically abnormal pulmonary arteries are a poor predictor of the presence of
clinically significant pulmonary hypertension. When significant pulmonary vascular abnormalities are
present in the absence of other histologic findings, then one may reasonably suggest the possibility of
pulmonary vascular disease, but the final arbiter is clinical evaluation with ultrasound evaluation, etc.
In this case, the presence of other pathologic abnormalities (scarred bronchioles) should lead one to be
cautious in ascribing significance to the pulmonary vascular changes. Pulmonary vascular thickening of this
type is very common in cases of chronic bronchiolitis/bronchiolar pathology regardless of cause and probably
are secondary. This probably explains (in part) the mosaic hypoprofusion pattern that is seen in
high-resolution CT scanning in cases of constrictive bronchiolitis. So at this point we can discount the
pulmonary vascular abnormalities as probably secondary .
Putting the Histologic Changes in Context:
Evaluation of medical lung disease requires some knowledge of the clinical and radiologic findings. The
findings in this case lead to different diagnostic considerations depending on the clinical findings. Here
are some scenarios.
Clinical history: A 61-year-old woman underwent biopsy of the right middle lobe for a persistent
localized infiltrate.
The histologic findings would be typical of middle lobe syndrome. In middle lobe syndrome there is chronic
atelectasis leading to recurring bouts of airway inflammation (with or without pneumonia) and distal
features of chronic bronchiolar injury as one sees here are common. The presence of granulomas would be a
good clue to the possibility of infection with MAI. MAI may be a commensal organism in chronic airway
disease and in some patients produces a low-grade infection. Radiologically the presence of nodular
opacities distal to bronchiectasis suggests infection with MAI
Clinical history: A patient with chronic bronchiectasis of the left lower lobe (or lingula) developed
nodular opacities radiologically and biopsy was perfonned.
Analogous to the situation described above, bronchiectasis anywhere in the lung may be associated with
distal bronchiolar pathology and secondary MAI infection. The histologic findings in the open biopsy in
this case would be quite typical MAI complicating localized chronic airway disease at any site.
Clinical history: A 61-year-old woman underwent open lung biopsy for diffuse pulmonary infiltrates.
She had an IgG subclass deficiency and recurrent pulmonary infections.
Lymphoid proliferations, both reactive and neoplastic, may be associated with granulomas. Patients with
acquired immunodeficiencies of a variety of types may develop recurrent pulmonary infections with resultant
airway pathology, including lymphoid hyperplasia with or without granulomas. The histologic features in
this case would be consistent with such a scenario, although one usually tends to see more prominent
germinal center formation.
Clinical history: A 61-year-old woman underwent open lung biopsy. She had recently spent $14,000
remodeling her master bath and had an indoor hot tub installed.
Hot tub lung has recently been described (see Khoor et al.). It is a syndrome associated with MAI
colonization of the hot tub and an inhalational pulmonary disease that is somewhat of a hybrid between an
infection and a hypersensitivity reaction. The current case would be compatible with such a possibility
although in hot tub lung the granulomas tend to be better formed, the lymphoid tissue less prominent, and
there is less chronic scarring.
Clinical history: A 61-year-old woman underwent open lung biopsy. She had interstitial lung disease
and bilateral hilar adenopathy said to be "classic" by the radiologist for sarcoidosis.
This case is not great for sarcoidosis. However, it would be difficult to exclude the possibility of
sarcoid, particularly superimposed on some airway scarring from some other cause. The relative lack of
lymphangitic involvement by the granulomas (while against sarcoidosis histologically) may occasionally be
encountered in sarcoidosis.
Clinical history: A 61-year-old woman underwent open lung biopsy. As a reprobate child she had enjoyed
sneaking into old factories and breaking fluorescent light bulbs and more recently had been employed
building chassis for computers. Her beryllium lymphocyte transformation test was pending.
Beryllium exposure is still relatively common and the latency between exposure and disease may be decades.
Broadly speaking, berylliosis looks like sarcoidosis histologically and for that reason this case would not
be a particularly good example of berylliosis but it would remain a possibility if the history and
immunology strongly suggested it. Sending peripheral blood for beryllium lymphocyte transformation testing
is indicated if the history suggested berylliosis.
Clinical history: A 61-year-old woman underwent open lung biopsy. She was an avid bird fancier and had
over 50 birds in her home but she indignantly denied letting them fly around loose and kept their cages
scrupulously clean with Acme bird cage cleaner.
Most cases of hypersensitivity pneumonitis tend to have more alveolar inflammation than is present here. In
addition, the granulomas are not quite as conspicuous and tend to be more scattered in the lung parenchyma.
Nevertheless, chronic hypersensitivity pneumonitis (bird fancier's lung) could produce a combination of
bronchiolar scarring, granulomas, and lymphoid tissue as are present in this case. High-resolution CT
scanning appearances, including diffuse micronodules, ground-glass change, and mosaic hypoprofusion may
provide strong radiologic evidence either for (or against) the possibility of hypersensitivity pneumontiis.
The real clinical history: A 61-year-old woman underwent open lung biopsy. She had a one-year history
of generalized fatigue with increased shortness of breath for two to three weeks. Radiologically there were
bilateral interstitial infiltrates and pleural effusions. She also reported dry mouth and dry eyes. ANA
was positive at 1:1280 and rheumatoid factor was positive. The clinical impression was Sjogren' s syndrome
with pulmonary involvement.
With that history one almost does not need a biopsy but the biopsy is indeed typical of Sjogren's syndrome
with bronchiolar involvement and associated granulomas. Among the collagen vascular disease, Sjogren's
syndrome is the most frequent one to be associated with granulomas. In addition, when patients have
co-existing pleural and parenchymal disease, collagen vascular disease should be one of the first
considerations. In this case the effusions were apparent clinically, although pleuritis was not apparent in
the open lung biopsy.
The pulmonary lesions associated with Sjogren's syndrome include:
Tracheobronchitis/submucosal gland atrophy with lymphoid infiltrate.
In this case the lymphoid infiltrates are not particularly prominent and not suggestive of a low-grade
lymphoma. Sjogren's syndrome is one of those instances, however where the distinction between reactive
lymphoid tissue and a low-grade lymphoma may be extremely difficult, if not impossible, unless one has the
full armamentarium of the hematopathologist at ones disposal. Some cases may be solved with paraffin
section kappa/lambda staining, whereas others require more sophisticated molecular or PCR studies. Even in
the best of hands, some cases remain unsolved and a descriptive diagnosis is necessary.
Could the case presented be considered an example of lymphocytic interstitial pneumonia (LIP)? My personal
preference is that this case is primarily a bronchiolitis with associated lymphoid tissue but since there is
some lymphoid tissue away from the bronchioles, one could argue that is a more diffuse lymphoid infiltrate
and as such within the spectrum of LIP. Since such a variety of patterns have been labeled LIP in the
literature, it is hopeless to try to come to any firm conclusions, and in cases such as this I tend to state
the problem and then try to dogmatically come to a solution.
Major Points of This Case
One cannot interpret medical lung biopsies without the clinical history .
Colby TV, Leslie KC. Small airway lesions. In: Cagle PT Ed. Diagnostic Pulmonary Pathology. Marcel
Dekker, New York, 2000; pp. 231-250.
Colby TV: Pulmonary pathology in patients with systemic autoimmune disease. Clinics in Chest Medicine
1998;19:587-612.
Coleman A, Colby TV: Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 12(7):514
-518, 1988.
Hansen LA, Prakash UBS, Colby TV: Pulmonary lymphomas in Sjogren's syndrome. Mayo Clin Proc
64:920-931, 1989.
Khoor A, Leslie KO, Tazelaar HD, Helmers RA, and Colby TV: Diffuse pulmonary disease caused by
nontuberculous mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol 2001 ; 115:755-762.
Kwon KY, Myers JL, Swensen SJ, Colby TV: Middle lobe syndrome: a clinicopathologic study of 21
patients. Hum Pathol 26:302-307 , 1995.
