follicular bronchiolitis

Definition: Follicular bronchiolitis refers to a pattern of numerous reactive lymphoid follicles in a peribronchial/peribronchiolar distribution.

It may occur either alone or as a secondary finding in association with bronchiectasis, chronic bronchitis, asthma, and other conditions.

Follicular bronchiolitis principally occurs in 3 settings:
 (1) underlying collagen vascular disease, especially rheumatoid arthritis;
 (2) underlying immunodeficiency—both congenital or acquired such as acquired immunodeficiency syndrome (AIDS), common variable immune deficiency, or others;
 (3) an idiopathic group.

Follicular bronchiolitis may occur in patients of any age, from infants to the older population. Patients without associated collagen vascular disease or immunodeficiency tend to be middle-aged or older (range, 38 to 77 years; average, 54 years).

Pulmonary symptoms include cough, dyspnea, fever, recurrent pneumonia, weight loss, or fatigue.

Results from pulmonary function studies may be normal or show a restrictive, obstructive, or mixed pattern. Serologic studies may show rheumatoid factor in patients with underlying collagen vascular disease.

Hypergammaglobulinemia or hypogammaglobulinemia may also be present.

The main findings on high-resolution CT scan consist of bilateral centrilobular nodules and sometimes peribronchial nodules. Nodules are often less than 3 mm in diameter but may be as large as 12 mm in some cases.

Pathology

In follicular bronchiolitis, numerous lymphoid follicles with associated reactive germinal centers are present around bronchi and bronchioles. The bronchiolar lumens are sometimes compressed. Lymphocytes extend into and permeate the adjacent bronchial or bronchiolar epithelium.

Foci of organizing pneumonia, obstructive pneumonia, or a bronchiolar intraluminal neutrophilic exudate are sometimes present as nonspecific associated findings.

A mild, often inconspicuous, associated interstitial inflammatory infiltrate is often present in adjacent alveolar septa. The interstitial inflammatory infiltrate is prominent in about 20% of cases. In these cases, there is histologic overlap with LIP.

In some cases, lymphoid follicles are present both around bronchi and bronchioles as well as in a lymphangitic distribution along the interlobular septa and pleura.

Cases with these features are sometimes described by the term diffuse lymphoid hyperplasia.

The reactive lymphoid follicles stain positively for pan B-cell markers (CD20, CD79a), whereas the interstitial component, when present, stains positively for pan T-cell markers (CD3). Staining for BCL-2 is absent in reactive germinal centers but present in interstitial T cells. A polyclonal pattern is present on polymerase chain reaction (PCR) for IgH gene rearrangement.26

Follicular bronchiolitis should be distinguished from LIP, nodular lymphoid hyperplasia, and low-grade BALT lymphoma. Although LIP may contain reactive germinal follicles, these are usually overshadowed by the prominent interstitial inflammatory infiltrate of T cells. Nonetheless, the histologic features of LIP and follicular bronchiolitis overlap, and the distinction may, in some cases, be arbitrary. Both patterns are considered part of the spectrum of lymphoid hyperplasia of the BALT.

Nodular lymphoid hyperplasia is easily distinguished from follicular bronchiolitis by its radiographic and histologic features. In contrast to follicular bronchiolitis, nodular lymphoid hyperplasia presents as a single or multiple mass on imaging studies. Histologically, the confluent proliferation of germinal centers with interfollicular plasma cells present in nodular lymphoid hyperplasia contrasts with the peribronchial/peribronchiolar distribution of reactive follicles in follicular bronchiolitis.

Low-grade B-cell lymphoma of BALT also generally presents as a well-demarcated solitary or multiple mass. Unlike either follicular bronchiolitis or nodular lymphoid hyperplasia, low-grade B-cell lymphoma of BALT is characterized by fairly monomorphous infiltrate of B lymphocytes.

Reactive germinal centers may be present but are randomly distributed and are less prominent than the monomorphous B-cell infiltrate. Areas of cartilage invasion and plaquelike invasion of the pleura may also be present—features not present in follicular bronchiolitis.

Analysis by PCR may be helpful in some cases, as approximately 60% to 70% of low-grade BALT lymphomas will show a clonal rearrangement of the immunoglobulin heavy chain gene, whereas a polyclonal pattern is always present in nodular lymphoid hyperplasia and follicular bronchiolitis.

Synopsis

 reactive lymphoid follicles adjacent to bronchi and bronchioles
 lymphoid follicles immunostain B-cell markers as CD20 or CD79a
 some feature may overlap with lymphoid interstitial pneumonitis (LIP)
 +/- organizing pneumonia
 +/- obstructive pneumonia
 +/- bronchiolar intraluminal neutrophilic infiltrate
 +/- lymphoid follicles in a lymphangitic distribution along interlobular septa and pleura (diffuse lymphoid hyperplasia)

Pathogenesis

The association of follicular bronchiolitis with immunodeficiency, collagen vascular disease, and peripheral eosinophilia suggests that it represents an expansion of the bronchus-associated lymphoid tissue in reaction to intrinsic and extrinsic stimuli.

This theory is supported by some animal models showing the development of follicular bronchiolitis upon exposure to Mycoplasma pneumoniae, pseudomonas, and intratracheal bacille Calmette-Guérin.

Prognosis and Treatment

The prognosis of idiopathic cases of follicular bronchiolitis is generally favorable. Most patients respond to steroids or azathioprine, although the patients may relapse.

Treatment and prognosis of patients with underlying collagen vascular disease or immunodeficiency is dependent upon the underlying condition.

See also

 chronic bronchiolitis

References

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 Nicholson, A. G. , A. C. Wotherspoon , T. C. Diss , et al. Reactive pulmonary lymphoid disorders. Histopathology 1995. 26 (5):405–412.

 Fishback, N. and M. Koss . Update on lymphoid interstitial pneumonitis. Curr Opin Pulm Med 1996. 2 (5):429–433.

 Abbondanzo, S. L. , W. Rush , K. E. Bijwaard , and M. N. Koss . Nodular lymphoid hyperplasia of the lung: a clinicopathologic study of 14 cases. Am J Surg Pathol 2000. 24 (4):587–597.

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 Bégueret, H. , B. Vergier , M. Parrens , et al. Primary lung small B-cell lymphoma versus lymphoid hyperplasia: evaluation of diagnostic criteria in 26 cases. Am J Surg Pathol 2002. 26 (1):76–81.

 Iwata, M. and A. Sato . A rat model of chronic bronchiolitis due to Pseudomonas aeruginosa—a histopathological study of bronchus-associated lymphoid tissue (BALT) [in Japanese]. Kansenshogaku Zasshi 1990. 64 (5):557–563.

 Davis, J. K. and G. H. Cassell . Murine respiratory mycoplasmosis in LEW and F344 rats: strain differences in lesion severity. Vet Pathol 1982. 19 (3):280–293.

 Iwata, M. and A. Sato . Morphological and immunohistochemical studies of the lungs and bronchus-associated lymphoid tissue in a rat model of chronic pulmonary infection with Pseudomonas aeruginosa. Infect Immun 1991. 59 (4):1514–1520.

 Travis, W. D. and J. R. Galvin . Non-neoplastic pulmonary lymphoid lesions. Thorax 2001. 56 (12):964–971. Yousem, S. A. , T. V. Colby , and C. B. Carrington . Follicular bronchitis/bronchiolitis. Hum Pathol 1985. 16 (7):700–706.