Mönckeberg sclerosis (MS) is a calcification of the medial

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1 Mönckeberg Sclerosis Revisited A Clarification of the Histologic Definition of Mönckeberg Sclerosis Robert G. Micheletti, BA; Gregory A. Fishbein, BA; Judith S. Currier, MD; Michael C. Fishbein, MD Context. Medial calcification of muscular arteries is known as Mönckeberg sclerosis (MS). Although this was first described in 1903, disagreement persists over its precise histologic appearance. Some, including Mönckeberg, have written that the media alone are calcified, whereas others maintain that both the media and internal elastic lamina (IEL) are involved. Since vascular calcification is of great interest to investigators and clinicians, defined criteria for classifying calcified arterial lesions are important. Objective. To clarify the histologic definition of MS with regard to calcification of the IEL. Design. We reviewed slides from 14 incisional and excisional surgical biopsies and autopsy specimens containing arteries with previously diagnosed MS. We looked specifically for medial and IEL calcification and used von Kossa, alizarin red, and trichrome/elastic stains to confirm our findings. We also performed a literature search on the histologic appearance of MS. Results. Both medial and IEL calcification were present in all specimens. Medial calcification extended alongside calcified IEL. In focal regions, calcification appeared limited to the IEL, with minimal medial calcification. Occasionally, calcified nodules in the media appeared separated from the IEL yet were connected to it in other planes of section. Despite these variations in appearance, IEL involvement was universal. Of 25 journal articles and texts, 10 state that MS involves the IEL with calcification, whereas 15 state or suggest that it does not. Conclusions. Our findings indicate MS involves both the IEL and media with calcification in spite of inconsistencies on this point in the medical literature. (Arch Pathol Lab Med. 2008;132:43 47) Mönckeberg sclerosis (MS) is a calcification of the medial layer of arteries that is most often found in the muscular arteries of the extremities and occasionally those of the viscera (Figure 1, A and B). First described in detail by J. G. Mönckeberg in 1903, 1 MS is a well-recognized, age-related phenomenon. Yet, its cause, clinical significance, and precise histologic appearance are not completely understood, nor are they agreed upon in the literature. Recent research has found that a host of stimulatory and inhibitory factors regulate vascular calcification, 2 but the precise mechanism of this process is unknown. In the past, MS has been linked to epinephrine, hypervitaminosis D, and autonomic neuropathy. 3 5 More recently, it has shown an association with diabetes mellitus, chronic renal failure, and osteoporosis. 2,6 8 For many years, MS was considered a completely benign condition, 3,9 usually noted as an incidental finding on radiographs of the extremities. Now, it is thought to lead to decreased arterial compliance and increased pulse pressure, left ventricular hypertrophy, peripheral vascular disease, and altered coronary perfusion. 8,10,11 Histologically, there is no disputing that MS involves calcification of the media. Yet, authors have disagreed Accepted for publication August 8, From the Department of Medicine, Division of Infectious Diseases (Mr Micheletti, Mr G. A. Fishbein, and Dr Currier) and the Department of Pathology and Laboratory Medicine (Dr M. C. Fishbein), David Geffen School of Medicine at the University of California, Los Angeles. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Robert G. Micheletti, BA, CARE Center, University of California, Los Angeles, 9911 W Pico Blvd, Suite 980, Los Angeles, CA ( mrobert@mednet.ucla.edu). about whether calcification is confined to the muscle of the media or also involves the internal elastic lamina (IEL). According to our translations of his original 1903 article, Mönckeberg himself wrote that in MS, real calcification of the IEL is never observed. Although medial calcification may extend to the IEL, it does not directly involve it. Many subsequent authors have shared this view, often relying on previous research and precedent in doing so. 4,12 Others have challenged this assertion, writing that MS can impact the IEL or may even begin there. 13 The product of a literature search on this topic can be seen in the Table, highlighting the continuing disagreement on this subject. Even this extensive list of references does not cover all opinions on this point. While the presence or absence of IEL calcification in MS may seem like a minor point, a clear understanding of MS histopathology has practical significance for researchers interpreting histologic findings of their own. In discussing IEL calcification of the temporal arteries, for instance, Nordborg et al 12 write that their findings should not be confused with Mönckeberg mediosclerosis... which is confined to the media and does not involve the intimal layer. (p567) Buchi et al 14 write, in turn, that the IEL calcification they observed in ophthalmic arteries [does] not represent Mönckeberg s medial calcification, as that disease consists of calcifications of the media. The calcifications they observed, on the other hand, originate along the IEL. (p41) The interpretations of these data underscore the importance of a precise and accurate definition of MS histopathology. Furthermore, where calcification begins in MS and what tissues it involves have broader implications for understanding the process of vascular calcification in MS and other conditions. Arch Pathol Lab Med Vol 132, January 2008 Mönckeberg Sclerosis Revisited Micheletti et al 43

2 Figure 1. A and B, Typical hematoxylin-eosin appearance of peripheral artery with so-called Mönckeberg medial sclerosis. In addition to the obvious medial calcification, there is calcification of the internal elastic lamina (arrows; original magnifications 12.5 [A] and 200 [B]). C and D, von Kossa stain of 2 less severe cases showing focal calcification of the internal elastic lamina (arrows) in addition to medial calcification that also involves the internal elastic lamina (arrowheads) (original magnifications 40 [C and D]). With this in mind, we reviewed slides from several previously diagnosed cases of MS in an effort to find evidence for or against IEL involvement. MATERIALS AND METHODS We reviewed slides of 14 tissue specimens from 12 patients, all of whom were diagnosed with Mönckeberg medial calcification on first review. Most of these specimens were collected as incisional biopsies or surgical excisions; two specimens were collected from a single autopsy. The original diagnoses were made between 2003 and 2007 by members of the Department of Pathology at the University of California at Los Angeles based on the presence of calcification of the vessel media. We reviewed all of these hematoxylin-eosin (H&E) stained slides to document the presence of medial or IEL calcification. We also prepared and reviewed alizarin red S, von Kossa, and trichrome/elastic stains in selected cases to help confirm the presence of medial calcification and determine the relationship of that calcification to the IEL. In addition, we conducted a thorough literature search on the subject of MS and IEL calcification to compare our findings to those reported in previous studies. The authors had full access to the study data and take responsibility for its integrity. All authors have read and agree to the manuscript as written. RESULTS The average age of the 12 patients with medial calcification was 74 years. Eight (67%) were women. Five (42%) were known to have diabetes mellitus. We observed medial calcification in slides from all 14 tissue specimens. Involved vessels included the dorsalis pedis, posterior tibialis, and radial arteries in 1 patient each. Unnamed small muscular arteries of the thyroid, foot, and knee were also involved in 1 patient each. Arteries of the breast and uterus were involved in 2 patients each, and the temporal artery was involved in 3 patients. Two patients had MS in more than one tissue. In one, the thyroid and uterus were involved, and in the other, both the dorsalis pedis and posterior tibialis arteries had medial calcification. In all specimens, we observed prominent, basophilic calcification of the medial layer on H&E-stained slides (Figures 1 and 2). Frequently, this calcification extended linearly around the circumference of the vessel. At other times, it was nodular and limited to a small portion of the media without linear extension. While we often observed fibrosis of the medial tissue in areas of calcification, there was little, if any, inflammation. Without exception, all specimens displayed involvement of the IEL with calcification. A close association of the IEL with medial calcification was apparent in sections with large medial calcium deposits (Figure 1, A and B) as well as those with only minimal medial calcification. In fact, in focal regions, calcification appeared not only to involve the IEL but to be limited to it (Figure 1, C and D). Conversely, there were focal areas of calcified nodules or bands in the center of the media that did not appear to come in contact with the IEL (Figure 2, A). However, closer review and serial sectioning revealed that these calcified areas did, in 44 Arch Pathol Lab Med Vol 132, January 2008 Mönckeberg Sclerosis Revisited Micheletti et al

3 Literature Search Regarding Internal Elastic Lamina (IEL) Calcification in Mönckeberg Medial Sclerosis (MS) Author Date IEL Involvement Quotation Mönckeberg No Subtle granules of calcium could be detected at the membrane elastica, but real calcification could never be observed Klotz Yes Changes usually lie in the middle of the media, but again may be situated along the inner border close to the intima so that the process of calcification involves the IEL MacCallum No The calcium is... in minute granules in the connective-tissue fibrils between the muscle cells.... The internal elastic lamella is stretched over these stony masses and often interrupted Silbert No First, fine granules of calcium salts are found near the [IEL] and in the connective tissue between the muscle fibers... often in the center of the media Anderson 25 * 1961 No Calcium is deposited in the form of plaques in the mid-portion of the media Anderson 24 * 1971 Yes Involving the media and internal elastic lamina of muscular arteries of the head, neck, and extremities Abramson Yes Changes are first recognizable in the [IEL] or the tissue upon which it rests... [it] acquires calcium on its surface and in its intrinsic structure. Often... occurs just beneath the [IEL] and spreads... into the media Abramson and 1984 No [MS is] probably related to the relative ischemia of the midzone of the media Dobrin 19 Peery and Miller Yes The media of the artery is primarily affected; the [IEL] is usually frayed and destroyed and calcium deposits occur chiefly in relation to this layer Bhagwat et al No The granules of calcium... are deposited in the areas of fatty degeneration in the media Lachman et al No The calcific deposits in Mönckeberg s calcinosis are located entirely within the medial layer of the arterial wall, and both internal and external elastic membranes are spared Huy et al Yes In rats initial deposition of calcium occurs in the [IEL]. Invasion of the tunica media occurs along the deep elastic fibres Muir No The earliest change is hyaline degeneration of the muscle fibers and fibrous tissue, usually starting about the middle of the media Kingma and Roy No In rats calcium deposits were seen near the internal elastic lamina Silver Yes There is calcification in the media, between and on the two elastic laminae. But, in a later passage, the process [MS] involves the media only Buchi et al No These lesions do not represent [MS], [which] consists of calcifications of the media... the calcifications we observed... [instead] originate along the IEL and later enlarge Young et al No There is fibrotic and calcified replacement of the tunica media. The internal and external elastic lamina may be involved in the fibrotic process Silver et al Yes Calcification may be confined to and may replace the internal elastic lamella or the medial smooth muscle Burke and Virmani Yes Medial calcification of Mönckeberg tends to begin in the internal elastic lamina Nordborg et al No Calcifications of the Mönckeberg type, located entirely within the media, were not found.... [MS] is confined to the media and does not involve the intimal layer Factor et al Yes MS consists of degenerative change that involves the [IEL] with spread of calcium and scar tissue into the media Speer and Giachelli No Typical morphology of such calcifications in the early stages of the disease is linear deposits along the elastic lamina throughout most of the medial width Schurgers et al No Major calcifications starting around the elastin fibers in the tunica media Qiao et al Yes Regions of calcification involve[e] the [IEL] and the media Lee et al No MS appear[s] as linear deposits along elastic lamina throughout most of the medial width, and in advanced lesions... the media is filled with circumferential rings * Note that the description of MS in relation to the IEL is different in these two editions of the Anderson text. The same photomicrograph used in both texts appears to show IEL involvement. The description of MS in relation to the IEL is also different in these two editions of the Abramson text, further illustrating the lack of clarity on this point. These two statements in the Silver text appear to contradict one another on the subject of IEL calcification in MS. fact, touch and involve the IEL in other areas or planes (Figure 2, A and B). At times, medial calcification appeared merely to be closely adjacent to the IEL. Yet, at least focally, calcification involved the IEL directly and was not only present near or along it, as some have suggested. 3,15,16 We frequently observed the IEL imbedded in calcified nodules as the IEL snaked through these calcifications (Figure 2, C and D). In most cases, however, medial calcification was concentrated next to and on the IEL, tracing its path around the vessel lumen (Figure 2, E and F). Reduplication and disruption of the IEL were frequent findings associated with medial and IEL calcification. In some cases, there was intimal fibrosis associated with the calcified and disrupted IEL. Alizarin red S, von Kossa, and trichrome/elastic stains confirmed our findings. COMMENT Our findings indicate that MS is defined by calcification of both the media and the IEL of muscular arteries. None of the 14 cases reviewed here, which we believe are typical of those called MS, had calcification limited to the media; IEL involvement was a universal finding. Despite these observations, inconsistencies on this point persist in the literature. Of 25 journal articles and texts shown in the Table, 10 state that MS involves the IEL with calcification, whereas 15 state or suggest that it does not. While Lachman et al 4 write that in MS both the internal Arch Pathol Lab Med Vol 132, January 2008 Mönckeberg Sclerosis Revisited Micheletti et al 45

4 Figure 2. Relationship of medial calcifications to internal elastic lamina. Note that all of the calcifications that involve the media also involve the internal elastic lamina. In A, a portion of the calcification only involves the media (arrowhead), but calcification also involves the internal elastic lamina (arrow). In C and D, the internal elastic lamina is imbedded in a nodule of calcification (arrow) (hematoxylin-eosin stain [A, C, and E] and trichrome/elastic tissue stains [B, D, and F]; original magnifications 12.5 [A and C], 200 [B], and 100 [D through F]). 46 Arch Pathol Lab Med Vol 132, January 2008 Mönckeberg Sclerosis Revisited Micheletti et al

5 and external elastic membranes are spared, Abramson s text states that the IEL acquires calcium on its surface and in its intrinsic structure. 17 Similarly, some have written that calcification in MS not only involves the IEL but tends to begin [there], 13 whereas others have argued that the changes associated with MS begin far from the IEL, in the middle of the media. 18 These excerpts represent diverse interpretations of MS histopathology that are difficult to reconcile. The origin of these differences is unclear, yet they can be partially explained by the varied appearance of MS we observed in these sections. For example, while many of the slides we reviewed showed calcification closely following and involving the contour of the IEL, other sections featured nodules and bands of calcium located primarily in the center of the media. While such nodules were connected to calcified IEL in other areas or planes of the section, they could create the impression of purely medial involvement when viewed alone. In some places, the IEL was immediately adjacent to medial calcification but did not appear to be calcified itself. In others, it was calcified even without adjacent medial involvement. While varied, together these findings present a full picture of MS in which the IEL is clearly involved. Since calcification in MS involves both structures, calcific deposits may begin on the IEL or in the media. One author describes changes that are first recognizable in the IEL a loss of undulation and a change in staining properties, then disruption and calcification of the membrane. 17 Others describe a process that begins instead in the media as a response to degeneration of smooth muscle cells, perhaps due to the relative ischemia of the midzone of the media We theorize that MS calcification may begin on or just beneath the IEL because of its involvement in all tissue sections we studied and because of the usually close association of medial calcification with it. However, it is important to recognize that, since MS is usually an incidental radiologic or pathologic diagnosis, it is impossible to observe disease progression histologically. Without fully understanding the pathogenesis of MS, attempts to explain its place of origin in the vessel wall are speculative. This inability to observe MS at all stages of its development is one of the prime limitations of our study. While our findings show that MS clearly does affect the IEL, we cannot prove that this is always the case, because we are not able to observe MS at its inception. Our small sample size of 14 tissue sections further limits our ability to draw wider conclusions about MS. Varied histologic findings, such as those described in this study, may partially explain the varied language sometimes used in the literature to define MS. It is interesting to note that several articles concerning MS include published photomicrographs that clearly show IEL involvement. 11,18,21 25 Yet, most of these articles do not include calcification of the IEL in their definition or discussion of MS. The uncertainty about what Mönckeberg reported could have been avoided had he too published photographs or drawings of the lesions he described. However, he did not, leaving us the unenviable task of concluding that what Mönckeberg originally described, which has become known as Mönckeberg medial sclerosis, does not accurately depict the pathologic entity we see today. Here we have offered evidence that MS is not limited to the media as many, including Mönckeberg, suggest, but rather involves both the IEL and the media. This research was supported by the Piansky Family Trust (Dr M. C. Fishbein). We acknowledge Longsheng Hong for her histology laboratory expertise. References 1. Monckeberg JG. Ueber die reine Mediaverkalkung der Extremitaetenarterien und ihr Verhalten zur Arteriosklerose. Virchows Arch Pathol Anat. 1903;171: Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res. 2006;99: Silbert SLH. Moenckeberg s sclerosis: a clinical entity. J Mt Sinai Hosp N Y. 1945;12 13: Lachman AS, Spray TL, Kerwin DM, Shugoll GI, Roberts WC. 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