—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 1 - Diffuse Panbronchiolitis

Philip T. Cagle
Baylor College of Medicine
Houston, TX


Click on each slide thumbnail image for an enlarged view
Clinical History
The patient was a 16 year old girl who developed a nonproductive cough and intermittent wheezing in the absence of any viral illness. She failed to respond to antibiotics and bronchodilators and progressively worsened over three months with severe exertional dyspnea. Pulmonary function tests showed severe airflow obstruction with no response to bronchodilators:

PFT Initial visit 1 month 3 months 1 year
FVC
(% predicted) 		1.80 L
(58%) 		1.35 L
(41%) 		1.12 L
(36%) 		1.00 L
(32%)
FEV1
(% predicted) 		0.56 L
(22%) 		0.50 L
(18%) 		0.40 L
(15%) 		0.39 L
(14%)
FEV1/FVC 32% 37% 36% 39%
TLC
(% predicted) 		4.31 L
(108%) 		5.88 L
(140%) 		5.82 L
(146%) 		Not available

She failed to respond to B-agonist inhalation and oral and intravenous theophylline and prednisone. No evidence of alpha-1-antitrypsin disease, cystic fibrosis or aspiration was found on clinical, radiologic or serologic evaluations. She had a weakly positive rheumatoid factor, but other work-up for collagen vascular disease was negative. A clinical diagnosis of bronchiolitis obliterans was made. She underwent a left thoracotomy and a diagnosis of "consistent with bronchiolitis obliterans" was made. She required intubation and mechanical ventilation on several occasions and was eventually transferred to The Methodist Hospital for lung transplantation.


Case 1 - Figure 1 - Gross cut surface of the explanted lung shows scattered small yellow nodules.
Case 1 - Figure 2 - Low power view of a bronchiole with mural infiltrates of foam cells and chronic inflammatory cells with exfoliation of foamy macrophages into the bronchiolar lumen.
Case 1 - Figure 3 - Low power of bronchiole with intramural foam cells.



Case 1 - Figure 4 - Medium power of same bronchiole as figure 3.
Case 1 - Figure 5 - High power of same bronchiole as figures 3 and 4.
Case 1 - Figure 6 - Bronchiolar lumen is narrowed and obstructed by foam cell infiltrate in the bronchiolar wall.



Case 1 - Figure 7 - Constrictive bronchiolitis with fibrous obliteration of the bronchiolar lumen.
Case 1 - Figure 8 - A tremendous number of foam cells fill the wall of this bronchiole.

The patient underwent transplantation of her heart and both lungs. Case 1 Figure 1 shows the gross cut surface of one of her native lungs. The remaining figures show microscopic views of sections taken from her native lungs. Figures 3, 4 and 5 are consecutively higher powers of one lesion.

Diagnosis: Diffuse Panbronchiolitis

Discussion
The patient was originally diagnosed with xanthomatous bronchiolitis obliterans. [1] Her histopathology/clinical features are those of an obstructive or constrictive bronchiolitis due to accumulation of foamy macrophages. The histopathologic features are suggestive of diffuse panbronchiolitis (DPB), a disease in which there is inflammation and foam cell infiltration of bronchioles. As noted below, DPB had not been recognized as arising in non-Japanese patients in North America at the time of her diagnosis in 1985. A number of pulmonary diseases can have small airway histopathology that is superficially similar to DPB, including variable inflammation and foam cell infiltration of bronchioles, and should be considered in the differential diagnosis.

This case of xanthomatous brocnhiolitis obliterans was reported in the Archives of Pathology and Laboratory Medicine in 1988. [1] The etiology of this patient's airway disease was not determined. Detailed studies of blood lipids did not reveal a hyperlipidemia other than a very mild nonspecific elevation of cholesterol and did not suggest a storage disease. Other underlying disease such as chronic infection, exposure to fumes, drug history or collagen vascular disease was not identified.

On cut surface, the lungs showed numerous punctate yellow nodules. The histopathology consists of narrowing of bronchiolar lumens by foamy, lipid-laden macrophages within the walls of bronchioles. Most of these are membranous (terminal) bronchioles and some of the small bronchi are similarly involved. The lumens of occasional bronchioles are completely obliterated by mature fibrous scar. The foam cells occasionally extend into adjacent interstitial spaces. Focal ulceration of bronchiolar and bronchial mucosa results in exfoliation of lipid-laden macrophages into bronchiolar and bronchial lumens. There is also extra-cellular lipid material and a lipid/cholesterol pneumonia probably representing a post-obstructive lipoid pneumonia observed on some slides.

The differential diagnosis for the histopathologic findings in this unusual case includes:

(1) Diffuse pan-bronchiolitis (DPB)
DPB is a distinctive, idiopathic sinobronchial syndrome characterized by progressive obstructive and suppurative airway disease. [2, 3, 4] Patients have chronic sinusitis in most cases, dyspnea on exertion, cough and eventually purulent sputum production, obstructive pattern on pulmonary function tests, bilateral small nodular opacities on chest x-ray and centrilobular lesions on HRCT. Patients typically have highly elevated serum cold agglutinins. Most cases occur in Japan, although it has been increasingly reported in other locations around the world, both in patients of Japanese and non-Japanese descent. [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22] An association with HLA-Bw54 has been reported in Japan and it has been proposed that HLA alleles or closely linked genes contribute to a genetic predisposition to DPB which may partly explain why this disorder is found primarily in Asians. [23, 24, 25] There is a slight male predominance and patients span a wide age range with a mean of 50 years. Colonization with Haemophilus influenzae or Pseudomonas aeruginosa is commonly observed and Pseudomonas infection may develop and is associated with poor prognosis. If untreated, DPB progresses to bronchiectasis and respiratory failure. Patients often have prolonged survival with chronic low-dose macrolide therapy, presumably as a result of non-specific anti-inflammatory effects of these antibiotics since they are effective even in the absence of Pseudomonas or other infection. [26-31] Baz et al [32] reported recurrence of DPB in a patient who underwent lung transplantation.

Grossly, the cut surfaces of the lungs show scattered 1 to 4 mm yellow nodules and may show findings of bronchiectasis and/or pneumonia. DPB is histopathologically characterized by:

  1. diffuse, bilateral chronic airway inflammation,
  2. bronchiolocentric, centrilobular chronic interstitial inflammation and
  3. accumulation of foam cells and
lymphoplasmacytic infiltrates throughout the full thickness of the walls of the respiratory bronchioles and their adjacent alveolar ducts and alveoli. [33] Involvement of the distal centrilobular conducting/gas exchange unit in DPB has been called the "PB unit lesion" and is the defining histopathologic feature of DPB. [33] Membranous bronchioles may be involved and may be ectatic. Follicular bronchiolitis, intraluminal acute inflammation, superimposed acute or organizing pneumonia, post-obstructive lipoid pneumonia and/or bronchiectasis may be present.

(2) Rheumatoid arthritis-associated bronchiolar disease (RA-BD)/DPB in rheumatoid arthritis
Although rheumatoid factor is often elevated in patients with DPB, relatively few patients have overt rheumatoid disease. However, several authors have reported DPB lesions in patients with rheumatoid arthritis. [34, 35, 36, 37, 38] Hayakawa et al [35] reported lesions that they referred to as RA-BD. RA-BD lesions differed from DPB in that:

  1. panbronchiolitis lesions were more common in DPB (68% versus )
  2. bronchiolar obliteration occurred at more proximal sites in RA-BD,
  3. long-term macrolide therapy had less effect in RA-BD and
  4. HLA-B was more frequent in DPB (50% versus 22.2%)
DPB or pulmonary lesions resembling DPB have also been described in association with microscopic polyangiitis, [39] Lambert-Eaton myasthenic syndrome and idiopathic thrombocytopenic purpura, [40] ulcerative colitis, [41] Churg-Strauss syndrome, [42] Sjogren's syndrome with malignant thymoma [43] and thymoma. [44]

(3) Human T-cell lymphotropic virus type 1 (HTLV-1)-associated bronchiolitis and DPB
Patients with HTLV-1 have occasionally been reported to have clinical and histopathologic findings of DPB. [45, 46, 47, 48] A study by Kadota et al [46] compared 15 cases of HTLV-1-associated bronchiolitis to 43 cases of DPB. HTLV-1-associated bronchiolitis was reported to have histopathologic features similar to DPB, but HTLV-1-assoicated bronchiolitis had a higher ratio of interleukin-2 receptor expression in T cells from BAL and did not respond as well to chronic macrolide therapy.

DPB or DPB-like lesions have been reported in patients with adult T-cell leukemia [49] and non-Hodgkin's lymphoma. [50]

(4) Pulmonary diseases with centrilobular interstitial foam cell accumulations
In 1994, Masatoshi Iwata, Tom Colby and Masanori Kitaichi published a classic paper on DPB and pulmonary diseases with centrilobular interstitial foam cell accumulations. [33] In this study, the authors found PB-like lesions in 20 of 1,336 wedge biopsies, resections or autopsies of various lung diseases that involve airways.

Although histopathologically resembling the PB unit lesions of DPB, the authors observed differences in their 20 cases and referred to the lesions in these cases as PB-like lesions. Therefore, similar to our case of xanthomatous bronchiolitis obliterans, these cases resembled DPB but using established criteria could be differentiated from DPB. Foam cells were found in the walls of alveolar ducts and, to a lesser extent, respiratory bronchioles. Membranous bronchioles or small bronchi showed the greatest accumulation of foam cells in cases of constrictive bronchiolitis, follicular bronchiolitis, bronchiectasis and cystic fibrosis typically associated with lymphoid hyperplasia and scarring. Other diseases showed focal poorly-developed PB-like lesions or occasional foci of interstitial foam cells associated with acute inflammation and intraluminal granulation tissue. A summary of these other lung diseases with PB-like lesions based on Iwata et al [33] is given below:

(5) Idiopathic bronchiolitis clinically mimicking DPB
Poletti et al [51, 52] screened all their patients presenting with clinical, pathophysiologic and radiologic pattern compatible with DPB and found 4 cases of DPB over a ten-year period. They also found 5 cases of idiopathic bronchiolitis that had clinical symptoms and HCT findings indistinguishable from those of DPB but lacking the typical histopathologic features of DPB.

(6) Eosinophilic bronchiolitis clinically mimicking DPB
Takayanagi et al [53] reported a patient who carried a diagnosis of DPB without response to erythromycin for 3 years. A diagnosis of eosinophilic bronchiolitis was eventually made on wedge biopsy of the lung tissue.

Summary:
This case of xanthomatous bronchiolitis obliterans has some clinical, gross and histopathologic features that suggest a diagnosis of DPB. DPB was first described in Japan in 1969 [54] and studied in a large nation-wide survey in Japan in 1983 [55] but was not recognized in North American patients until several years later. [22] Our patient underwent lung transplant and was diagnosed with xanthomatous bronchiolitis obliterans in 1985, a number of years before the disease was recognized as occurring in North America. Although treatment of patients with macrolide antibiotics for infections began in 1983, Kudoh et al [56]reported that chronic low-dose macrolide antibiotic therapy improved the course of DPB through mechanisms not related to treatment of infection. Therefore, it is not surprising that our patient did not receive macrolide therapy even if a diagnosis of DPB had been suspected in 1985.

This patient did not have any of the conditions mentioned above that are associated with PB-like lesions. Indeed, the accumulation of foamy macrophages in bronchiolar walls is very dramatic in some of the bronchioles in sections of her lung tissue and would not likely represent the more modest foam cell accumulations secondary to other conditions.

This case may be best considered a variant of classic DPB. In addition to an absence of some of the expected clinical features, this case differs from classic DPB in that:

  1. The membranous bronchioles and small airways are more involved by the foam cell infiltrates than expected in DPB and
  2. The relative amount of both mural chronic inflammation and intra-luminal acute inflammation are less than is typical of DPB.
These differences may be related to the short course of the disease in a young patient, since most studied cases represent long-standing disease in middle-aged to older adults. Disease variations due to geoethnic differences may also be factors.

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