The sarcoid granuloma: ‘epithelioid’ or ‘lymphocytic-epithelioid’ granuloma?
© Kosjerina et al.; licensee BioMed Central Ltd. 2012
Received: 17 May 2012
Accepted: 20 June 2012
Published: 20 June 2012
This study aims to analyze the structure and quantities of cellular elements in sarcoid granulomas.
We investigated 34 transbronchial lung biopsy samples obtained from 34 sarcoid patients. The quantity and composition of the cellular elements inside a granuloma were determined by the quantitative stereometry method, employing the numerical density as a stereological method.
A total of 102 sarcoid granulomas were analyzed. The central part of all granulomas was occupied by epithelioid cells. Besides these, giant cells, lymphocytes, macrophages and plasma cells were also seen. The mean numerical density of all the cells in the central part of a sarcoid granuloma was 111,751 mm-3. Lymphocytes prevailed in number, exceeding the total count of all other cells. With a mean numerical density of 74,321 mm-3, lymphocytes were twice as numerous as both epithelioid cells and macrophages with a mean numerical density of 37,193 mm-3.
Lymphocytes are the predominant cell type in the central part of a sarcoid granuloma, significantly exceeding both epithelioid cells and macrophages in number, raising the question if the term “epithelioid granuloma”, routinely used to designate sarcoid granulomas, is correct, or if it would be more logical to call them “lymphocytic-epithelioid granulomas” instead.
This study was supported by the Serbian Ministry of Science and Environmental Protection Grant Number 175006/2011.
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 . Granulomas are structured masses composed of lymphocytes and macrophage-derived cells, which assume an epithelioid aspect [2, 3]. They are composed of focal collections of macrophages and their derivatives, as well as of lymphocytes.
The central part of a granuloma is composed of macrophages, modified macrophages, epithelioid cells and giant cells, with scattered, predominately CD4+ T, lymphocytes between them . The peripheral part of a granuloma is predominantly occupied by lymphocytes, fibroblasts, sparse macrophages and fibrocytes. CD4+ T lymphocytes predominate in the inner layer of the granuloma periphery and CD8+ T lymphocytes in the outer one . B lymphocytes are usually very rare in a granuloma . Caseous necrosis is absent, while central necrosis, as a granular acidophilic focus without nuclear detritus, may be found . This focus usually produces a periodic acid Schiff (PAS) positive reaction, suggesting the fibrinoid necrosis is involved here.
The purpose of the investigation was to analyze the structure and quantities of cellular elements in sarcoid granulomas.
The material of the investigation included 34 transbronchial lung biopsy samples obtained from 34 sarcoid patients - 22 (64.7%) females and 12 (35.3%) males, mean age 43.2 years. Each specimen was embedded in paraffin and five microns thick sections were stained with hematoxylin-eosin. All patients had stage II sarcoidosis. The diagnosis of sarcoidosis was based on histological, clinical and radiological evidence. The morphologic diagnosis of pulmonary sarcoidosis relies on three main findings: the presence of tight, well-formed granulomas with a rim of lymphocytes and fibroblasts in the outer margin; a perilymphatic interstitial distribution of the granulomas; and exclusion of an alternative cause .
High resolution computed tomography was used to diagnose stage (Stage II – bilateral hilar lymphadenopathy and diffuse pulmonary infiltrations).The granulomas were interactively divided into a central part and a peripheral part. The central part of the granuloma consists of sessile macrophages, which have been transformed into epithelioid cells, and by fusion form the multi-nucleated Langhans giant cells. In the periphery lie activated T-lymphocytes, predominantly CD4+ lymphocytes, some CD8+ lymphocytes and a few B lymphocytes .
The quantity and composition of the cellular elements inside a granuloma were determined by the quantitative stereometry method [10–12]. The multi-purpose Weibel's test system M42 was used as an instrument for stereometric analysis.
Numerical density was utilized in the study as a stereological method. The numerical density is a relative stereological variable denoting the number of particles in a space unit. The numerical density dimension is mm-3.
in which NA is the numerical areal density of the particles, DF represents the depth of focus, and D the mean diameter of the particles.
in which “λ” represents the light wave length (550 nm), “n” is the refractive index of the specimen, i.e. practically of the mounting medium, and close to the index of glass, 1.52, and “NA” represents the numerical aperture of respective magnification lens .
In 34 transbronchial lung biopsy samples examined, a total of 102 sarcoid granulomas were found (1–11 in a biopsy sample). Three sarcoid granulomas per biopsy were registered on average. Most of the granulomas were solitary and only 7 were coalesced. In these 7 coalesced granulomas, a total of 20 solitary granulomas were found.
The mean numerical density of all the cells in the central part of sarcoid granulomas was 111,751 mm-3, ranging from 43,897 to 197,986 mm-3.
Lymphocytes prevailed in number, being double the number of both epithelioid cells and macrophages. This is a statistically significant difference (p < 0.05).
Both epithelioid cells and macrophages were exclusively found in the central region of all examined granulomas. Their numerical density ranged from 15,379 to 65,477 mm-3, or 37,193 mm-3 on average.
In addition to epithelioid cells, giant cells were also found in the central region of 63 (61.76%) granulomas, while 39 (38.23%) of the examined granulomas contained no giant cells.
Lymphocytes were observed in both the central and peripheral region of all examined granulomas. The numerical density of the lymphocytes localized in the central granuloma region ranged from 28,518 to 131,436 mm-3, with the mean numerical density of 74,321 mm-3.
Cellular elements in the central region of sarcoid granuloma
Epithelioid cells and Macrophages
Our data show that the most prevalent population in the central part of sarcoid granuloma are lymphocytes, a rather unexpected finding supported by a new morphometric approach.
Analyzing a biopsy sample of a sarcoid patient, Soler and Basset  found mature epithelioid cells in the central granuloma region, terming it a follicle. He considered epithelioid cells to have been the main component of a sarcoid granuloma.
Carrington  examined 49 sarcoid samples and expressed the density of cell populations according to a semiquantitave score of density (0 - a normal finding; 10 - the most intensive change). He found epithelioid cells were the predominant component (6.0 degrees), followed by lymphocytes (5.0 degrees), and giant cells (4.8 degrees).
Ferluga  analyzed 14 bronchobiopsy sarcoid samples and established “the epithelioid cells as the predominant cellular component of sarcoid granulomas, except in the terminal, sclerotic stage of the disease”. Fusse et al.  found a great number of epithelioid cells in the central part of a sarcoid granuloma.
Basset et al.  reported that epithelioid cells were (at least regarding their quantity) the predominant component of sarcoid granulomas.
Cardoso et al. , in an analysis of 31 biopsy samples of cutaneous sarcoidosis, found epithelioid cells present in 100% of the cases, and multinucleate giant cells in 30 biopsies (97%). Lymphoid cells were also seen in all cases, but only in a small number in 22 biopsies (71%).
Rosen reported: “Lymphocytes are often numerous and are well visualized by light microscope in the peripheral cellular mantle of the sarcoid granuloma. Although lymphocytes are seldom conspicuous in the central portion of granuloma, they can be visualized readily by electron microscopy” .
All these authors have reported that epithelioid cells were the major or basic element of a sarcoid granuloma. A long list of other authors [22–56] have called sarcoid granuloma “epithelioid granuloma”, which means they acknowledge the fact that epithelioid cells represent the fundamental and most numerous cell element in sarcoid granuloma, while Carrington , Baset et al.  and Cardoso et al.  have explicitly stated that epithelioid cells predominated in quantity in a sarcoid granuloma.
This is not in correlation with our findings of lymphocytes as the predominating cells in the central part of a sarcoid granuloma, significantly exceeding the number of epithelioid cells.
We would try to explain this by an image. Let us imagine a room with 10 ping-pong balls, as well as 10 large balls of 1 m in diameter, randomly thrown around. If we now make parallel imagined cross-sections from the ceiling to the floor at 2 m distance, according to the theory of probability, we would cut two or more large balls, and at the same time only one or none of the ping-pong balls. Analyzing now the obtained cross-sections, we would wrongly conclude that there are more large balls in the room, although the number of large and ping-pong balls in the room is in fact the same. Figuratively, ping pong balls stand for lymphocytes, large balls represent epithelioid cells and the imagined cross-sections of the room are histological cuts.
Lymphocytes are the predominant cell type in the central part of a sarcoid granuloma, significantly exceeding both epithelioid cells and macrophages in number. This difference is statistically significant.
It is justifiable to question the term “epithelioid granulomas” which has been used to designate sarcoid granulomas. Would it not be preferable to term these granulomas “lymphocytic-epithelioid granulomas” instead? We fervently hope this question will be answered soon.
We are very well aware of the fact that it is not only the count of the cells, but also their function and role that are important, and all must be considered in the pathogenesis of sarcoidosis.
Written informed consent was obtained from the patient for publication of 227 this report and any accompanying images.
Relating to Figure 1, courtesy of Dr Yale Rosen, SUNY Downstate Medical Center, Brooklyn, NY, USA.
This study was supported by the Serbian Ministry of Science and Environmental Protection Grant Number 175006/2011.
- Ma Y, Gal A, Koss MN: The pathology of pulmonary sarcoidosis: update. Semin Diagn Pathol. 2007, 24: 150-161. 10.1053/j.semdp.2007.06.002.View ArticlePubMedGoogle Scholar
- Danila E, Zurauskas E: Diagnostic value of epithelioid cell granulomas in bronchoscopic biopsies. Intern Med. 2008, 47: 2121-2126. 10.2169/internalmedicine.47.1452.View ArticlePubMedGoogle Scholar
- Zissel G, Prasse A, Müller-Quernheim J: Sarcoidosis -immunopathogenetic concepts. Semin Respir Crit Care Med. 2007, 28: 3-14. 10.1055/s-2007-970329.View ArticlePubMedGoogle Scholar
- Oliver SJ, Kikuchi T, Krueger JG, Kaplan G: Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement. Clin Immunol. 2002, 102: 225-236. 10.1006/clim.2001.5173.View ArticlePubMedGoogle Scholar
- Kita S, Tsuda T, Sugisaki K, Miyazaki E, Matsumoto T: Characterization of distribution of T lymphocyte subsets and activated T lymphocytes infiltrating into sarcoid lesions. Intern Med. 1995, 34: 847-855. 10.2169/internalmedicine.34.847.View ArticlePubMedGoogle Scholar
- Williams WJ: Granulomas in the diagnosis of sarcoidosis - state of art. Sarcoidosis and other granulomatous disorders: proceedings of the XI World Congress on Sarcoidosis and Other Granulomatous Disorders, Milan, 6–11 September 1987. Edited by: Grassi C, Rizzato G, Pozzi E. 1988, Excerpta Medica, Amsterdam; New York, 661-673.Google Scholar
- Hsu RM, Connors AF, Tomashefski JF: Histologic, microbiologic, and clinical correlates of the diagnosis of sarcoidosis by transbronchial biopsy. Arch Pathol Lab Med. 1996, 120: 364-368.PubMedGoogle Scholar
- American Thoracic Society: Statement on sarcoidosis. Am J Respir Crit Care Med. 1999, 160: 736-755.View ArticleGoogle Scholar
- Milman N, Andersen CB, Baslund B, Loft A, Iversen M: Does tumor necrosis factor-alfa inhibitor infliximab induce histological resolution of pulmonary sarcoid grannulomas?. Clin Respir J. 2007, 1: 106-113. 10.1111/j.1752-699X.2007.00023.x.View ArticlePubMedGoogle Scholar
- Weibel ER: Stereology – a bridge between morphology and physiology. Acta Stereologica. 1982, 1: 23-33.Google Scholar
- Kalisnik M: Temelji stereologije. Acta Stereologica. 1985, 4: 1-148.Google Scholar
- Weibel ER: Morphometry of the human lung. 1963, Academic Press, Inc, New YorkView ArticleGoogle Scholar
- Weibel ER, Gomez DM: A principle for counting tissue structures on random sections. J Appl Physiol. 1962, 17: 343-348.PubMedGoogle Scholar
- Berek M: Grundlagen der Tiefenwahrnehmung im Mikroskop. Ber Ges Naturw Marburg. 1927, 62: 189-223.Google Scholar
- Soler P, Basset F: Morphology and distribution of the cells of a sarcoid granuloma: ultrastructural study of serial sections. Ann N Y Acad Sci. 1976, 278: 147-160. 10.1111/j.1749-6632.1976.tb47026.x.View ArticlePubMedGoogle Scholar
- Carrington CB: Structure and function in sarcoidosis. Ann N Y Acad Sci. 1976, 278: 265-283. 10.1111/j.1749-6632.1976.tb47038.x.View ArticlePubMedGoogle Scholar
- Ferluga D: Histomorfološki aspekti sarkoidoze različitih organa. Pluć Bol Tuberk. 1973, 1: 40-54.Google Scholar
- Fuse Y, Imazekin I, Asakawa M, Hiraga Y, Shimada Y, Mikami R, Osada H, Hayakawa K: Ultrastructural study of sarcoid granulomas: Lymphocyte alterations within sarcoid granulomas. VIII Conference on Sarcoidosis. 1980, AOPL, Cardiff, 19-22.Google Scholar
- Basset F, Soler P, Hance A: Sarcoidosis - from granuloma formation to fibrosis. Sarcoidosis and other granulomatous disorders: proceedings of the XI World Congress on Sarcoidosis and Other Granulomatous Disorders, Milan, 6–11 September 1987. Edited by: Grassi C, Rizzato G, Pozzi E. 1988, Excerpta Medica, Amsterdam, New York, 235-246.Google Scholar
- Cardoso JC, Cravo M, Reis JP, Tellechea O: Cutaneous sarcoidosis: a histopathological study. J Eur Acad Dermatol Venereol. 2009, 23: 678-682. 10.1111/j.1468-3083.2009.03153.x.View ArticlePubMedGoogle Scholar
- Rosen Y: Sarcoidosis. Pulmonary pathology. Edited by: Dail DH, Hammar SP. 1988, Springer-Verlag, New YorkGoogle Scholar
- Vital A, Lagueny A, Ferrer X, Louiset P, Canron MH, Vital C: Sarcoid neuropathy: clinico-pathological study of 4 new cases and review of the literature. Clin Neuropathol. 2008, 27: 96-105.View ArticlePubMedGoogle Scholar
- Terasaki F, Fujita M, Shimomura H, Tsukada B, Otsuka K, Otsuka K, Katashima T, Ikemoto M, Kitaura Y: Enhanced expression of myeloid-related protein complex (MRP8/14) in macrophages and multinucleated giant cells in granulomas of patients with active cardiac sarcoidosis. Circ J. 2007, 71: 1545-1550. 10.1253/circj.71.1545.View ArticlePubMedGoogle Scholar
- Noor A, Knox KS: Immunopathogenesis of sarcoidosis. Clin Dermatol. 2007, 25: 250-258. 10.1016/j.clindermatol.2007.03.002.View ArticlePubMedGoogle Scholar
- Campo I, Morbini P, Zorzetto M, Tinelli C, Brunetta E, Villa C, Bombieri C, Cuccia M, Agostini C, Bozzi V, Facoetti A, Ferrarotti I, Mazzola P, Scabini R, Semenzato G, Pignatti PF, Pozzi E, Luisetti M: Expression of receptor for advanced glycation end products in sarcoid granulomas. Am J Respir Crit Care Med. 2007, 175: 498-506.View ArticlePubMedGoogle Scholar
- Dubaniewicz A, Trzonkowski P, Dubaniewicz-Wybieralska M, Dubaniewicz A, Singh M, Myśliwski A: Comparative analysis of mycobacterial heat shock proteins-induced apoptosis of peripheral blood mononuclear cells in sarcoidosis and tuberculosis. J Clin Immunol. 2006, 26: 243-250. 10.1007/s10875-006-9011-9.View ArticlePubMedGoogle Scholar
- Nishie M, Mori F, Suzuki C, Ogawa M, Kurahashi K, Kaimori M, Wakabayashi K: Disseminated intraparenchymal microgranulomas in the brainstem in central nervous system sarcoidosis. Neuropathology. 2005, 25: 361-364. 10.1111/j.1440-1789.2005.00623.x.View ArticlePubMedGoogle Scholar
- Pujol RM, Gallardo F, Servitje O, Martí RM, Bordes R, García-Muret MP, Estrach MT, Nomdedeu JF: Peripheral T-cell lymphoma with secondary epithelioid granulomatous cutaneous involvement: a clinicopathologic study of four cases. J Dermatol. 2005, 32: 541-548.View ArticlePubMedGoogle Scholar
- Wan Muhaizan WM, Swaminathan M, Daud MS: Cardiac sarcoidosis: two cases with autopsy findings. Malays J Pathol. 2004, 26: 59-63.PubMedGoogle Scholar
- Ardehali H, Howard DL, Hariri A, Qasim A, Hare JM, Baughman KL, Kasper EK: A positive endomyocardial biopsy result for sarcoid is associated with poor prognosis in patients with initially unexplained cardiomyopathy. Am Heart J. 2005, 150: 459-463. 10.1016/j.ahj.2004.10.006.View ArticlePubMedGoogle Scholar
- Torralba KD, Quismorio FP: Sarcoid arthritis: a review of clinical features, pathology and therapy. Sarcoidosis Vasc Diffuse Lung Dis. 2003, 20: 95-103.PubMedGoogle Scholar
- Echigo T, Saito A, Takehara K, Takata M, Hatta N: Coexistence of micrometastatic melanoma cells and sarcoid granulomas in all regional lymph nodes in a patient with acral melanoma. Clin Exp Dermatol. 2003, 28: 375-376. 10.1046/j.1365-2230.2003.01279.x.View ArticlePubMedGoogle Scholar
- Quinones-Hinojosa A, Chang EF, Khan SA, McDermott MW: Isolated trigeminal nerve sarcoid granuloma mimicking trigeminal schwannoma: case report. Neurosurgery. 2003, 52: 700-705.View ArticlePubMedGoogle Scholar
- Loh AH, Wee KP: Sudden death due to granulomatous myocarditis: a case of sarcoidosis?. Ann Acad Med Singapore. 2002, 31: 805-807.PubMedGoogle Scholar
- Okabe T: Origin of epithelioid cells in sarcoid granuloma. Nihon Rinsho. 2002, 60: 1714-1719.PubMedGoogle Scholar
- Tsuda T: Characterization of distribution of immunological competent cells in sarcoid granuloma. Nihon Rinsho. 2002, 60: 1720-1727.PubMedGoogle Scholar
- Vannemreddy PS, Nanda A, Reddy PK, Gonzalez E: Primary cerebral sarcoid granuloma: the importance of definitive diagnosis in the high-risk patient population. Clin Neurol Neurosurg. 2002, 104: 289-292. 10.1016/S0303-8467(02)00012-4.View ArticlePubMedGoogle Scholar
- Gambichler T, Herde M, Hoffmann K, Stücker M, Altmeyer P, Jansen T: Sarcoid variant of actinic granuloma: is it annular sarcoidosis?. Dermatology. 2001, 203: 353-354. 10.1159/000051792.View ArticlePubMedGoogle Scholar
- O'Riordan E, Willert RP, Reeve R, Kalra PA, O'Donoghue DJ, Foley RN, Waldek S: Isolated sarcoid granulomatous interstitial nephritis: review of five cases at one center. Clin Nephrol. 2001, 55: 297-302.PubMedGoogle Scholar
- Nowak DA, Gumprecht H, Widenka DC, Stölzle A, Lumenta CB: Solitary sarcoid granulomatosis mimicking meningioma. J Neurosurg. 2000, 93: 897-10.3171/jns.2000.93.5.0897.View ArticlePubMedGoogle Scholar
- Mempel M, Flageul B, Suarez F, Ronet C, Dubertret L, Kourilsky P, Gachelin G, Musette P: Comparison of the T cell patterns in leprous and cutaneous sarcoid granulomas. Presence of Valpha24-invariant natural killer T cells in T-cell-reactive leprosy together with a highly biased T cell receptor Valpha repertoire. Am J Pathol. 2000, 157: 509-523. 10.1016/S0002-9440(10)64562-2.PubMed CentralView ArticlePubMedGoogle Scholar
- Zimmermann-Belsing T, Christensen L, Hansen HS, Kirkegaard J, Blichert-Toft M, Feldt-Rasmussen U: A case of sarcoidosis and sarcoid granuloma, papillary carcinoma, and Graves' disease in the thyroid gland. Thyroid. 2000, 10: 275-278. 10.1089/thy.2000.10.275.View ArticlePubMedGoogle Scholar
- Ishioka S, Wiwien HW, Hiyama K, Maeda A, Yamakido M: New monoclonal antibodies against the epithelioid cells in sarcoid granulomas. Exp Lung Res. 1999, 25: 663-670. 10.1080/019021499269981.View ArticlePubMedGoogle Scholar
- Popper HH: Epithelioid cell granulomatosis of the lung: new insights and concepts. Sarcoidosis Vasc Diffuse Lung Dis. 1999, 16: 32-46.PubMedGoogle Scholar
- Elias WJ, Lanzino G, Reitmeyer M, Jane JA: Solitary sarcoid granuloma of the cerebellopontine angle: a case report. Surg Neurol. 1999, 51: 185-190. 10.1016/S0090-3019(97)00497-7.View ArticlePubMedGoogle Scholar
- Iyonaga K, Suga M, Ichiyasu H, Yamamoto T, Hiraga Y, Ando M: Measurement of serum monocyte chemoattractant protein-1 and its clinical application for estimating the activity of granuloma formation in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 1998, 15: 165-172.PubMedGoogle Scholar
- Kitamura Y, Motoi M, Terada T: An autopsy case of ancient sarcoidosis associated with severe fibrosis in the liver and heart. Pathol Int. 1998, 48: 536-541. 10.1111/j.1440-1827.1998.tb03945.x.View ArticlePubMedGoogle Scholar
- Fukuda T, Sato K, Tachikawa S, Ohnuki K, Ohtani H, Suzuki T: Mucosa-associated lymphoid tissue lymphoma coexisting with epithelioid granulomas in the stomach of a patient with systemic sarcoidosis. Pathol Int. 1997, 47: 870-875. 10.1111/j.1440-1827.1997.tb03720.x.View ArticlePubMedGoogle Scholar
- Bergeron A, Bonay M, Kambouchner M, Lecossier D, Riquet M, Soler P, Hance A, Tazi A: Cytokine patterns in tuberculous and sarcoid granulomas: correlations with histopathologic features of the granulomatous response. J Immunol. 1997, 159: 3034-3043.PubMedGoogle Scholar
- Tews DS, Pongratz DE: Immunohistological analysis of sarcoid myopathy. J Neurol Neurosurg Psychiatry. 1995, 59: 322-325. 10.1136/jnnp.59.3.322.PubMed CentralView ArticlePubMedGoogle Scholar
- Ito Y, Suzuki T, Mizuno M, Morita Y, Muto E, Ichida S, Hananouchi M, Yuzawa Y, Matsuo S: A case of renal sarcoidosis showing central necrosis and abnormal expression of angiotensin converting enzyme in the granuloma. Clin Nephrol. 1994, 42: 331-336.PubMedGoogle Scholar
- Iwai K, Takemura T, Kitaichi M, Kawabata Y, Matsui Y: Pathological studies on sarcoidosis autopsy. II. Early change, mode of progression and death pattern. Acta Pathol Jpn. 1993, 43: 377-385.PubMedGoogle Scholar
- Takayama K, Nagata N, Miyagawa Y, Hirano H, Shigematsu N: The usefulness of step sectioning of transbronchial lung biopsy specimen in diagnosing sarcoidosis. Chest. 1992, 102: 1441-1443. 10.1378/chest.102.5.1441.View ArticlePubMedGoogle Scholar
- MacRury SM, McQuaker G, Morton R, Hume R: Sarcoidosis: association with small bowel disease and folate deficiency. J Clin Pathol. 1992, 45: 823-825. 10.1136/jcp.45.9.823.PubMed CentralView ArticlePubMedGoogle Scholar
- Chilosi M, Mombello A, Lestani M, Menestrina F, Fiore-Donati L, Cipriani A, Zambello R, Semenzato G: Immunohistochemical characterization of sarcoid granuloma: differentiation antigens and adhesion molecules. Sarcoidosis. 1991, 8: 171-172.PubMedGoogle Scholar
- Tetikkurt C, Tetikkurt S, Ozdemir I, Bayar N: Round atelectasis in sarcoidosis. Multidiscip Resp Med. 2011, 6: 180-182.View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.