The pathology of pulmonary sarcoidosis: update

https://doi.org/10.1053/j.semdp.2007.06.002Get rights and content

Sarcoidosis is a multi-system disease of unknown etiology, usually affecting the respiratory tract and other organs, and is characterized by the formation of nonnecrotizing epithelioid granulomas. The diagnosis depends on a combination of a typical clinicoradiological presentation, the finding of nonnecrotizing epithelioid granulomas in a tissue biopsy, and exclusion of other possible diseases, especially those of infectious etiology. The granulomas contain epithelioid cells, giant cells, CD4+ T cells in their center, and CD8+ T lymphocytes and B lymphocytes at their periphery. The granulomas are present in a lymphatic pattern around bronchovascular structures and, because of this, may show angioinvasion. The bronchial involvement produces a high diagnostic yield for transbronchial and endobronchial biopsies in this disease. Finally, small amounts of fibrinoid necrosis may occur within granulomas of sarcoidosis and do not exclude the diagnosis. Larger amounts suggest either infection or the rare disease necrotizing sarcoid granulomatosis (NSG). A number of cytoplasmic structures/inclusions can be identified within the granulomas of sarcoidosis, including asteroid bodies, Schaumann’s bodies, calcium oxalate crystals, and Hamazaki–Wesenberg bodies; the last two of these can cause difficulties in differential diagnosis. Extra-pulmonary sarcoid can be an important factor in prognosis. Involved sites include (in decreasing frequency): skin, endocrine organs, extra-thoracic lymph nodes, neurologic sites, eyes, liver, spleen, bone marrow, cardiac, ear/nose/throat, parotid/salivary, muscles, bones/joint, and kidney. NSG is a controversial variant of sarcoidosis consisting of granulomatous pneumonitis with sarcoid-like granulomas, variable amounts of necrosis, and granulomatous vasculitis. The lesions are most often confined to lung, and they usually appear as multiple nodules or nodular infiltrates, but occasionally as solitary or unilateral nodules ranging up to 5 cm in diameter. Nodular sarcoidosis is rare, varying from 1.6% to 4% of patients with sarcoidosis, and, as the name suggests, it shows radiographic nodules measuring 1 to 5 cm in diameter that typically consist of coalescent granulomas. Lung transplantation can be used in selected patients with fibrotic late-stage sarcoidosis. There is a high reported frequency of recurrence of disease in the pulmonary allograft, ranging from 47% to 67%, but recurrence is usually not clinically significant. Studies of the pathogenesis of sarcoidosis suggest that it is a chronic immunological response produced by a genetic susceptibility and exposure to specific environmental factors.

Section snippets

Gross appearance

The lung shows no gross abnormalities in the very early stages of sarcoidosis. Still, as the disease advances, small nodules become visible in the pleura and within the lung parenchyma (Figure 1).2 On section of the lung, the nodules are white, usually 1 to 2 mm in diameter, granular, and distributed in a lymphangitic pattern, namely along subpleural and pleural areas, interlobular septa and around bronchovascular regions—regions with a rich lymphatic supply. In more advanced cases, the lungs

Histopathology

Microscopically, the different stages of the disease in lung show different appearances. The earliest stage of the disease has a mild nonspecific interstitial mononuclear inflammatory infiltrate or alveolitis that precedes granuloma formation.3, 5, 6, 7 However, the pathologic diagnosis of sarcoidosis requires the presence of multifocal, nonnecrotizing epithelioid granulomas, which occur somewhat later in the development of the disease. The granulomas are of uniform histologic stage, and they

Inclusions in sarcoidosis

A number of nonspecific cytoplasmic structures/inclusions can be identified within the granulomas of sarcoidosis (Figure 7). These inclusions may falsely lead pathologists to the conclusion that the granulomas are of foreign-body origin.

Asteroid bodies are star-shaped spiculated structures that typically occur within multinucleated giant cells (Figure 7). They are seen in only 2% to 9% of sarcoidal granulomas.7 By electron microscopy, these structures consist of an amorphous matrix embedded

Diagnosis of sarcoidosis

Sarcoidosis is a clinicopathologic diagnosis, and it remains a diagnosis of exclusion of other conditions that can produce similar granulomas. Currently, the diagnosis of sarcoidosis depends on a combination of three different features: a typical clinico-radiological presentation; the histologic presence of nonnecrotizing epithelioid granulomas in a tissue biopsy; and exclusion of other possible diseases, especially those of infectious etiology, which may produce nonnecrotizing or minimally

Extra-pulmonary sarcoidosis

Sarcoidosis is a systemic disease that can affect many organs. The diagnosis can be delayed in patients who have isolated extra-pulmonary findings, in those in whom extra-pulmonary manifestations precede or overshadow the pulmonary disease, or in those who have unusual sites or patterns of extra-pulmonary disease.

There are several examples of unusual patterns of organ involvement in sarcoidosis. Subcutaneous sarcoidosis31 or scleritis32 can be the first manifestation of systemic disease at

Necrotizing sarcoidoid granulomatosis and nodular sarcoidosis

Necrotizing sarcoid granulomatosis (NSG) is both controversial and rare. Liebow described this disease in 1973.39 The current consensus is that most cases are examples of sarcoidosis with necrosis and vasculitis, but we are of the opinion that the definition, which is based on descriptive histopathology, is such as to allow for more than one entity.

Radiologically, NSG can present as bilateral nodules, solitary nodules, or a military pattern preceding the formation of nodules.40 Microscopically,

Lung transplantation for sarcoidosis

Lung transplantation is an ultimate option in selected patients with fibrotic late-stage sarcoidosis. Of interest, there is a high reported frequency of recurrence of disease in the pulmonary allograft, ranging from 47% to 67%.66, 67, 68, 69 However, recurrent granulomas usually have no significant impact on lung function or on short-term outcome.69

Of 4721 patients who had lung transplantation in the United States, 2.8% of them had a pretransplantation diagnosis of sarcoidosis.70 Patients who

Differential diagnosis of sarcoidosis

Because of the lack of a specific and currently available pathognomonic test for sarcoidosis and its diversity of clinical expression, diagnosis of this disease remains one of exclusion of other disorders that may show similar clinical features and pathologic changes on biopsy.

In a recent review article of the pathology of interstitial lung disease, sarcoidosis is placed in the category of “interstitial lung diseases dominated by a nodular pattern,”72 in which the differential diagnosis

Studies on the etiology and pathogenesis of sarcoidosis

Although there have been many advances in the understanding of sarcoidosis, its etiology and pathogenesis remain unknown. Current thinking is that sarcoidosis has more than one etiology, which may in turn lead to different patterns of the disease. Put in another way, the disease is viewed as a chronic immunological response produced by a genetic susceptibility and exposure to specific environmental factors.

Racial and ethnic factors affect disease frequency and prognosis.88 In the United States,

References (113)

  • Y.S. Wasfi et al.

    A new tool to assess sarcoidosis severity

    Chest

    (2006)
  • A. Churg et al.

    Necrotizing sarcoid granulomatosis

    Chest

    (1979)
  • F. Le Gall et al.

    Necrotizing sarcoid granulomatosis with and without extrapulmonary involvement

    Path Res Pract

    (1996)
  • D.R. Chittock et al.

    Necrotizing sarcoid granulomatosis with pleural involvementClinical and radiographic features

    Chest

    (1994)
  • F. Brevet et al.

    [Necrotizing sarcoid granulomatosis with ocular, pulmonary and cerebral involvement]

    Rev Med Interne

    (1993)
  • R.C. Beach et al.

    Necrotizing sarcoid granulomatosis with neurologic lesions in a child

    J Pediatr

    (1980)
  • L.B. Strickland-Marmol et al.

    Necrotizing sarcoid granulomatosis mimicking an intracranial neoplasm: clinicopathologic features and review of the literature

    Mod Pathol

    (2000)
  • O.P. Sharma et al.

    Nodular sarcoidosis: an unusual radiographic appearance

    Chest

    (1973)
  • E. Onal et al.

    Nodular pulmonary sarcoidosisClinical, roentgenographic, and physiologic course in five patients

    Chest

    (1977)
  • A.F. Shorr et al.

    Sarcoidosis, race, and short-term outcomes following lung transplantation

    Chest

    (2004)
  • K.O. Leslie

    Pathology of interstitial lung disease

    Clin Chest Med

    (2004)
  • R. Tambouret et al.

    The clinical application and cost analysis of fine-needle aspiration biopsy in the diagnosis of mass lesions in sarcoidosis

    Chest

    (2000)
  • A.A. Gal et al.

    Granulomatous Pneumocystis carinii pneumonia complicating hematopoetic cell transplantation

    Pathol Res Pract

    (2002)
  • C. Saltini et al.

    Beryllium disease

    Am J Med Sci

    (2001)
  • H. Brincker

    Sarcoid reactions in malignant tumors

    Cancer Treat Rev

    (1986)
  • M.E. Kreider et al.

    Relationship of environmental exposures to the clinical phenotype of sarcoidosis

    Chest

    (2005)
  • O.P. Sharma

    Tumor necrosis factor polymorphism in sarcoidosis

    Chest

    (2001)
  • W.D. Travis et al.

    Non-neoplastic disorders of the lower respiratory tract

  • R.G. Crystal et al.

    Pulmonary sarcoidosis: a disease characterized and perpetuated by activated T-lymphocytes

    Ann Intern Med

    (1981)
  • T.M. Ulbright et al.

    Solitary necrotizing granulomas of the lung: differentiating features and etiology

    Am J Surg Pathol

    (1980)
  • Y. Rosen et al.

    Sarcoidosis: from the pathologist’s vantage point

    Pathol Annu

    (1979)
  • P.D. Thomas et al.

    Current concepts of the pathogenesis of sarcoidosis

    Am Rev Respir Dis

    (1987)
  • A.A. Gal et al.

    The pathology of sarcoidosis

    Curr Opin Pulm Med

    (2002)
  • H. Nunes et al.

    Pulmonary sarcoidosis

    Allergy

    (2005)
  • E. Rodriguez et al.

    Sarcoidosis-associated bronchiolitis obliterans organizing pneumonia

    Arch Intern Med

    (2001)
  • G.M. Blackmon et al.

    Pulmonary sarcoidosis: a mimic of respiratory infection

    Semin Respir Infect

    (1995)
  • J.F. Beekman et al.

    Spectrum of pleural involvement in sarcoidosis

    Arch Intern Med

    (1976)
  • N.T. Soskel et al.

    Pleural involvement in sarcoidosis

    Curr Opin Pulm Med

    (2000)
  • S. Nagai et al.

    Heterogeneity of pulmonary fibrosis: interstitial pneumonias and sarcoidosis

    Curr Opin Pulm Med

    (2001)
  • L.S. Newman et al.

    Sarcoidosis

    N Engl J Med

    (1997)
  • Y. Rosen

    Sarcoidosis

  • D. Visscher et al.

    Significance of crystalline inclusions in lung granulomas

    Mod Pathol

    (1988)
  • J.D. Reid et al.

    Calcium oxalate in sarcoid granulomasWith particular reference to the small ovoid body and a note on the finding of dolomite

    Am J Clin Pathol

    (1988)
  • P.J. Symmans et al.

    Calcium oxalate crystal deposition in epithelioid histiocyties of granulomatous lymphadenitis: analysis by light and electron microscopy

    Histopathology

    (1995)
  • E. Uzaslan et al.

    Cockade-like structures in alveolar macrophages in extrinsic allergic alveolitis

    Respiration

    (2005)
  • W.F. Doyle et al.

    The nature of yellow-brown bodies in peritoneal lymph nodes

    Arch Pathol

    (1973)
  • J.Y. Ro et al.

    Yellow-brown (Hamazaki-Wesenberg) bodies mimicking fungal yeasts

    Arch Pathol Lab Med

    (1987)
  • R.M. Hsu et al.

    Histologic, microbiologic, and clinical correlates of the diagnosis of sarcoidosis by transbronchial biopsy

    Arch Pathol Lab Med

    (1996)
  • J.T. Annema et al.

    Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of sarcoidosis

    Eur Respir J

    (2005)
  • D. Dursun et al.

    Scleritis associated with sarcoidosis

    Ocul Immunol Inflamm

    (2004)
  • Cited by (98)

    • Update on cardiac sarcoidosis

      2023, Trends in Cardiovascular Medicine
    • Cardiac sarcoidosis: Diagnosis confirmation by bronchoalveolar lavage and lung biopsy

      2018, Respiratory Medicine
      Citation Excerpt :

      Our primary outcome measure was the number of positive biopsies or BAL cellular analyses consistent with extra-cardiac sarcoidosis in patients with suspected CS. Positive biopsies were defined as the presence of microscopic non-necrotizing epithelioid granulomas consistent with sarcoidosis in the absence of mycobacterial and fungal infection [26]. Lung parenchymal biopsies were performed by transbronchial biopsy (TBLB; n = 25) or thoracoscopic surgical lung wedge biopsy (SLB; n = 1).

    • Imaging of Pulmonary Sarcoidosis—A Review

      2024, Journal of Clinical Medicine
    • The inflammatory spectrum of cardiomyopathies

      2024, Frontiers in Cardiovascular Medicine
    View all citing articles on Scopus
    View full text