lymphocytic interstitial pneumonia

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 HPC:318 - Lymphocytic interstitial pneumonia (LIP)

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 Wikimedia: Lymphocytic interstitial pneumonia

Definition: LIP is a form of ’idiopathic’ interstitial pneumonia.

Lymphocytic interstitial pneumonia (LIP) is a lymphoproliferative disorder characterized by dense interstitial accumulation of lymphocytes and plasma cells.

Hypergammaglobulinemia is present in a high percentage of affected individuals.

Although the cellular infiltrate is usually dffuse, nodular lesions are often seen as well. Granulomas (not shown) and blood vessel involvement may also be associated with LIP.

Although LIP may be idiopathic it is known to occur in association with a variety of autoimmune disorders, infections (P. jiroveci, HIV, hepatitis B, E-B virus), collagen vascular diseases, immunodeficiency states (AIDS, SCID) and others.

When the diagnosis of LIP is being considered appropriate studies to establish clonality in order to rule out a low grade B cell lymphoma must be undertaken.

LIP should not be diagnosed unless the possiblity of lymphoma has been reasonably excluded.

Lymphoid interstitial pneumonia (LIP) is part of a spectrum of pulmonary lymphoproliferative disorders that range from benign, small, and airway-centered cellular infiltrates (follicular bronchiolitis, nodular lymphoid hyperplasia) to low-grade malignant lymphoma.

Most of the cases occur in patients with underlying autoimmune disease or immunodeficiency.

The characteristic high-resolution computed tomography findings consist of diffuse ground-glass opacities, ill-defined centrilobular nodules, bronchovascular thickening, interlobular septal thickening, and scattered thin-walled cysts. The cysts may be seen in up to 80% of the patients and are typically few in number and measure less than 3 cm in diameter. (16915074)

Lymphocytic interstitial pneumonitis is a pattern of interstitial lung disease characterized by a polymorphous inflammatory infiltrate that diffusely expands alveolar septa.

First described by Liebow and others in the early 1970s, it is currently considered, along with follicular bronchiolitis, as part of the spectrum of pulmonary lymphoid hyperplasia.

The LIP pattern may occur in association with underlying collagen vascular disease, immunodeficiency, allogeneic bone marrow transplantation, and drug reactions.

In associated collagen vascular diseases, LIP is a common manifestation of Sjögren syndrome, but may also occur with rheumatoid arthritis40 and systemic lupus erythematosus.

Lymphocytic interstitial pneumonitis has also been observed in patients with AIDS and common variable immunodeficiency.

For children younger than 13 years who are infected with the human immunodeficiency virus (HIV), LIP is considered an AIDS-defining illness.

Rarely, LIP may be idiopathic.

In recent years, the diagnosis of LIP has been greatly restricted. Many of the cases formerly interpreted as LIP would now be considered examples of cellular NSIP.

Lymphocytic interstitial pneumonitis affects persons in a broad age range, from infants to the elderly. However, most patients are middle-aged with a mean age at diagnosis of 52 to 56 years. Symptoms are nonspecific and include cough and dyspnea. The onset of symptoms is often gradual and may be present for years before diagnosis.

Pulmonary function studies usually show a restrictive pattern. Carbon monoxide diffusing capacity is reduced. Arterial blood gases may show hypoxemia. A serum dysproteinemia consisting of a polyclonal hypergammaglobulinemia is present in up to 80% of patients. Some patients have hypogammaglobulinemia.

High-resolution CT scans show bilateral areas of ground-glass opacity accompanied by centrilobular and subpleural nodules and patchy bronchovascular and interlobular septal thickening. A common associated finding is the presence of cysts, which, rarely, may dominate the radiographic findings.

Findings on chest x-ray are less specific and show bilateral lower zone reticular or reticulonodular infiltrates.

Pathology

The LIP pattern consists of a dense polymorphous interstitial inflammatory infiltrate that diffusely expands alveolar septa (Figure 3, a and b; Table 3). The infiltrate is composed of lymphocytes admixed with variable numbers of histiocytes and plasma cells. A component of follicular bronchiolitis is often present, consisting of reactive lymphoid follicles along bronchovascular bundles.

There is substantial overlap between the patterns of follicular bronchiolitis and LIP such that, in about 20% of cases, the distinction is arbitrary.

Other histologic features that may be present include intraepithelial lymphocytes, type II pneumocyte hyperplasia, focal lymphocytic infiltration of vessel walls, foci of organizing pneumonia, loose nonnecrotizing granulomas, and occasional isolated giant cells. Interstitial fibrosis of varying degree may be present. Foci of amyloid may also occur occasionally.

On immunohistochemistry, interstitial lymphocytes are composed predominantly of T cells and stain positively for CD3 (pan T-cell marker). In contrast, areas of follicular bronchiolitis are composed of B cells and stain positively for CD20 and CD79a (pan B-cell markers).26 Associated interstitial plasma cells show a polyclonal pattern of expression for κ and λ light chains and a polyclonal pattern on PCR for the IgH chain gene.26,52

The differential diagnosis of LIP is broad. Histologic considerations include follicular bronchitis/bronchiolitis, cellular NSIP, low-grade B-cell lymphomas (low-grade B-cell lymphoma of BALT and pulmonary involvement by chronic lymphocytic leukemia), hypersensitivity pneumonitis, and infection.

Consideration of clinical and histologic features along with immunohistochemical and molecular studies, when appropriate, usually allows these disorders to be distinguished.

While LIP shows a predominantly interstitial infiltrate of T cells (CD3+), follicular bronchiolitis consists of peribronchial reactive lymphoid follicles expressing B-cell markers (CD20+).26 Although extension of lymphocytes into the adjacent interstitium may be present in follicular bronchiolitis, it is usually not extensive.23 Nonetheless, in occasional cases with overlapping histologic features, the distinction may be somewhat arbitrary.

In contrast to the polymorphous interstitial infiltrate in LIP, interstitial patterns of low-grade B-cell lymphoma have a monomorphous appearance. Areas of cartilage invasion or plaquelike involvement of the pleura may be present in low-grade B-cell lymphoma but are generally absent in LIP. Likewise, Dutcher bodies are present in some cases of low-grade B-cell lymphoma but are not a feature of LIP.

On immunohistochemistry, low-grade B-cell lymphoma expresses pan B-cell markers (CD20, CD79a), whereas the interstitial infiltrate in LIP consists predominantly of T cells (CD3).

Finally, in most, but not all cases of low-grade B-cell lymphoma, immunohistochemical and molecular studies show a clonal population of B cells.

The presence of a clonal population can be demonstrated by either light chain restriction on immunohistochemistry for κ and λ chains or a clonal rearrangement on PCR for the IgH chain gene. A clonal population is not present in cases of LIP.

Other forms of interstitial lung disease, such as cellular NSIP and hypersensitivity pneumonitis, must be distinguished from LIP. The distinction of cellular NSIP and LIP patterns is based primarily on the degree of cellular infiltration.

The infiltrate in LIP is generally much more extensive than in cellular NSIP, such that it expands and distorts the underlying alveolar framework. In addition, reactive lymphoid follicles are also often present. Nonetheless, many cases formerly regarded as LIP would now be considered within the spectrum of cellular NSIP.

Poorly formed granulomas may be observed in both LIP and hypersensitivity pneumonitis. However, the interstitial infiltrate in hypersensitivity pneumonitis is patchy and less dense, with a peribronchiolar distribution.

Infectious process can occasionally mimic an LIP pattern. Pneumocystis jiroveci pneumonia or cytomegalovirus may show a prominent interstitial mononuclear infiltrate. Accordingly, before considering a diagnosis of LIP on a surgical biopsy specimen, special stains as well as careful assessment for viral cytopathic effect should be performed.

Synopsis

 massive diffuse interstitial infiltrates composed of lymphocytes intermixed with plasma cells and histiocytes
 dense polymorphous interstitial inflammatory infiltrate composed of lymphocytes, histiocytes, plama cells
 numerous lymphocytes and plasma cells within pulmonary interstitial tissue
 marked numbers of lymphocytes and plasma cells within interstitial tissue
 occasionally, granulomas form with giant cell reaction.
 dense and diffuse alveolar septal infiltrates associating lymphocytes, plasmocytes, plasmacytoid cells and macrophages
 +/- multinucleated giant cells
 +/- small ill-defined epithelioid granuloma
 +/- interstitial lymphocytes
 +/- type 2 pneumocyte hyperplasia
 +/- foci of organizing pneumonia
 +/- loose non-necrotizing granulomas
 +/- occasional giant cells
 +/- interstitial fibrosis
 +/- foci of amyloid
 +/- microscopic honeycomb remodeling
 +/- BALT hyperplasia (pulmonary lymphoid hyperplasia)
 component of follicular bronchiolitis often present
 diffuse pulmonary cysts (16915074)

Associations

 pulmonary infections

• Pneumocystis jiroveci pneumonia
• Epstein-Barr virus infection
• HIV infection
• Legionella pneumonia
• tuberculosis
• Mycoplasma
• Chlamydia

 hypersensitivity pneumonitis (extrinsic allergic alveolitis)

 dysimmunity and auto-immunity (39%)

• Sjögren syndrome
• rheumatoid arthritis
• systemic lupus erythematosus
• Hashimoto thyroiditis
• myasthenia gravis
• pernicious anemia
• drug-associated lung injury
• toxin-associated lung injury
• bone marrow transplantation
• hypogammaglobulinemia
• celiac sprue
• primary biliary cirrhosis

 immunodeficiency diseases (14%)

• HIV infection +/- DILS
• genetic immunodeficiency syndromes
  • common variable immunodeficiency (CVID) (10607809)
  • agammaglobulinemia

 allogenic bone marrow transplantation (pulmonary GVHD)
 drug reactions
 pulmonary alveolar microlithiasis

Pathogenesis

Lymphocytic interstitial pneumonitis is considered, along with follicular bronchiolitis, as part of a spectrum of hyperplasia of the BALT. The observation of LIP in association with Sjögren syndrome, EBV infection, and HIV infection likely reflects sequella of longstanding chronic antigen stimulation.

Prognosis and Treatment

Approximately 33% to 50% of patients with LIP die within 3 to 5 years. However, prognosis depends somewhat on the associated underlying disease condition. In some patients the disease stabilizes or resolves. Mortality is the result of progressive honeycomb fibrosis or infectious complications. Low-grade B-cell lymphoma may develop in rare cases.

Treatment consists of steroids or other immunosuppressive agents, with variable results. Single and multidrug antiretroviral therapy may induce remission in HIV-infected patients.

Differential diagnosis

 NSIP
 low-grade lymproliferative disease
 hypersensitivity pneumonitis
 atypical mycobacterial infections
 pulmonary drug reactions

Links

 Lymphocytic interstitial pneumonia (LIP) at the Yale Rosen Collection

See also

 other pulmonary lymphoid hyperplasias

• BALT hyperplasia (follicular bronchiolitis)
• pulmonary nodular lymphoid hyperplasia

 lymphoid pneumonitis

• nonspecific interstitial pneumonitis (NSIP)

References

 Lymphocytic interstitial pneumonia and other lymphoproliferative disorders in the lung. Nicholson AG. Semin Respir Crit Care Med. 2001 Aug;22(4):409-22. PMID: 16088689

 Swigris JJ, Berry GJ, Raffin TA, Kuschner WG. Lymphoid interstitial pneumonia: a narrative review. Chest. 2002 Dec;122(6):2150-64. PMID: 12475860

 Liebow, A. A. and C. B. Carrington . Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia. Med Clin North Am 1973. 57 (3):809–843.

 Koss, M. N. , L. Hochholzer , J. M. Langloss , W. D. Wehunt , and A. A. Lazarus . Lymphoid interstitial pneumonia: clinicopathological and immunopathological findings in 18 cases. Pathology 1987. 19 (2):178–185.

 Swigris, J. J. , G. J. Berry , T. A. Raffin , and W. G. Kuschner . Lymphoid interstitial pneumonia: a narrative review. Chest 2002. 122 (6):2150–2164.

 Perreault, C. , S. Cousineau , G. D’Angelo , et al. Lymphoid interstitial pneumonia after allogeneic bone marrow transplantation: a possible manifestation of chronic graft-versus-host disease. Cancer 1985. 55 (1):1–9.

 Parambil, J. G. , J. L. Myers , R. M. Lindell , E. L. Matteson , and J. H. Ryu . Interstitial lung disease in primary Sjögren syndrome. Chest 2006. 130 (5):1489–1495.

 Uziel, Y. , B. Hen , M. Cordoba , and B. Wolach . Lymphocytic interstitial pneumonitis preceding polyarticular juvenile rheumatoid arthritis. Clin Exp Rheumatol 1998. 16 (5):617–619.

 Yood, R. A. , D. M. Steigman , and L. R. Gill . Lymphocytic interstitial pneumonitis in a patient with systemic lupus erythematosus. Lupus 1995. 4 (2):161–163.

 Benisch, B. and B. Peison . The association of lymphocytic interstitial pneumonia and systemic lupus erythematosus. Mt Sinai J Med 1979. 46 (4):398–401.

 Travis, W. D. , C. H. Fox , K. O. Devaney , et al. Lymphoid pneumonitis in 50 adult patients infected with the human immunodeficiency virus: lymphocytic interstitial pneumonitis versus nonspecific interstitial pneumonitis. Hum Pathol 1992. 23 (5):529–541.

 Grieco, M. H. and P. Chinoy-Acharya . Lymphocytic interstitial pneumonia associated with the acquired immune deficiency syndrome. Am Rev Respir Dis 1985. 131 (6):952–955.

 Morris, J. C. , M. J. Rosen , A. Marchevsky , and A. S. Teirstein . Lymphocytic interstitial pneumonia in patients at risk for the acquired immune deficiency syndrome. Chest 1987. 91 (1):63–67.

 Couderc, L. J. , P. Hervé , P. Solal-Celigny , et al. Interstitial lymphoid pneumonia and polyadenopathies in patients infected with the LAV/HTLV III virus [in French]. Presse Med 1986. 15 (24):1127–1130.

 Kohler, P. F. , R. D. Cook , W. R. Brown , and R. L. Manguso . Common variable hypogammaglobulinemia with T-cell nodular lymphoid interstitial pneumonitis and B-cell nodular lymphoid hyperplasia: different lymphocyte populations with a similar response to prednisone therapy. J Allergy Clin Immunol 1982. 70 (4):299–305.

 Teirstein, A. S. and M. J. Rosen . Lymphocytic interstitial pneumonia. Clin Chest Med 1988. 9 (3):467–471.

 Centers for Disease Control (CDC) Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR Morb Mortal Wkly Rep 1987. 36 (15):225–230. 235–236.

 Johkoh, T. , N. L. Muller , H. A. Pickford , et al. Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology 1999. 212 (2):567–572.

 Silva, C. I. , J. D. Flint , R. D. Levy , and N. L. Muller . Diffuse lung cysts in lymphoid interstitial pneumonia: high-resolution CT and pathologic findings. J Thorac Imaging 2006. 21 (3):241–244.

 Teruya-Feldstein, J. , D. W. Kingma , A. Weiss , et al. Chemokine gene expression and clonal analysis of B cells in tissues involved by lymphoid interstitial pneumonitis from HIV-infected pediatric patients. Mod Pathol 2001. 14 (10):929–936.