REVIEW

Elastophagocytosis: Underlying mechanisms andassociated cutaneous entities

Jinane El-Khoury, MD, Mazen Kurban, MD, and Ossama Abbas, MDBeirut, Lebanon

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Elastophagocytosis is the phagocytosis of elastic fibers that can microscopically be seen in the cytoplasm ofhistiocytes, multinucleated giant cells, or both. Generally believed to be a characteristic feature of certaingranulomatous disorders such as annular elastolytic giant cell granuloma or elastolytic disorders such asmid-dermal elastolysis, this feature has also been described in other cutaneous inflammatory conditions,cutaneous malignancies, infectious entities, and secondary to certain medications. The list of diseases thatcan exhibit this peculiar finding on histopathology is long. In this review we attempt to shed light on theavailable literature concerning the pathogenesis of this phenomenon and the plethora of skin conditionsthat exhibit elastophagocytosis. ( J Am Acad Dermatol 2014;70:934-44.)

Key words: elastolysis; elastophagocytosis.

Abbreviations used:

AEGCG: annular elastolytic giant cell granulomaGA: granuloma annulareGMF: granulomatous mycosis fungoidesGSS: granulomatous slack skinIGD: interstitial granulomatous dermatitisMDE: mid-dermal elastolysisMF: mycosis fungoidesMMP: matrix metalloproteinase

Elastophagocytosis is the phagocytosis ofelastic fibers that can microscopically beseen in the cytoplasm of histiocytes, multi-

nucleated giant cells, or both (Fig 1).1-3 This phe-nomenon may be primary or secondary and we willreview the available literature concerning pathogen-esis and diagnostic value of this phenomenon(Table I).

ETIOPATHOGENESISVery few studies have looked at the phenomenon

of elastophagocytosis with an aim at elucidating itsetiopathogenesis.1

Elastic fibers in elastophagocytosisElastic fibers, which are made up of an inner core

of cross-linked elastin proteins surrounded by fibril-lin microfibrils, form an architecturally distinct mesh-work that confers to the skin its elastic recoilproperties.4 The turnover of elastin in an adult isvery low with its half-life probably exceeding thelifespan of the individual.5 This has clinical implica-tions; once these fibers are lost, the skin losesdefinitively its elasticity. In elastophagocytosis,several studies have looked at the ultrastructuralstate of the phagocytosed elastic fibers by trans-mission electron microscopy.1-6 Some studies

the Dermatology Department, American University of Beirut

edical Center.

ing sources: None.

licts of interest: None declared.

pted for publication December 5, 2013.

int requests: Ossama Abbas, MD, Dermatology Department,

merican University of Beirut Medical Center, PO Box 11-0236,

demonstrated that both normal and degeneratedelastin fibers can be seen being actively phagocy-tosed by macrophages in MDE.7-9 This indicates thatelastophagocytosis can be directed against bothnormal and abnormal fibers (Fig 2).

Several factors may contribute to elastic fiberdamage leading to a proinflammatory cascade andelastophagocytosis.9 One possibility may be thatdefective elastic tissue synthesis may lead to elastol-ysis such as seen in x-linked recessive cutis laxa.10

Defective copper metabolism has also been linked toelastolysis in acquired cutis laxa.11 Other implicatedprocesses include autoimmunity and postinflamma-tory elastolysis, in which elastin degradation occursas a result of elastinolytic enzymes.12-14 Elastinolyticenzymes, which include aspartic, cysteine, metallo-,and serine proteinases, can be found in various

Riad El Solh/Beirut 1107 2020, Lebanon. E-mail:

ossamaabbas2003@yahoo.com.

Published online January 21, 2014.

0190-9622/$36.00

� 2014 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2013.12.012

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micro-organisms and in snake venom, macrophages,trophoblasts, and pancreatic, polymorphonuclear,and tumor cells. Elastases found in granulocytes areserine proteinases packaged in azurophilic gran-ules.14 Their role in skin disease is not very welldescribed although they may contribute to elastol-ysis and elastophagocytosis that accompanies

CAPSULE SUMMARY

d Elastophagocytosis is the phagocytosisof elastic fibers by histiocytes. It canoccur with various conditions.

d The possible underlying mechanismsleading to elastophagocytosis arediscussed.

d In this review, the different genetic oracquired conditions whereelastophagocytosis may be encounteredare described.

intense neutrophilic inflam-mation in Sweet syndrome.15

Macrophage elastases arematrix metalloproteinases(MMPs) with lower affinityto elastin.14 MMP-12, pro-duced by macrophages, isincreased in skin aging, con-tributes to photo-aged hu-man skin through thecleavage of elastin and otherextracellular matrix compo-nents, and its expression isalso increased in areasdevoid of elastic fibers ingranulomatous skin dis-

eases.16,17 Other types of MMPs, especially MMP-9,have also been implicated in skin disease.18,19

However, elastin degradation does not neces-sarily lead to phagocytosis. For instance, photo-aged and chronologically aged skin, which exhibitsdegenerative elastin changes, is seldom associatedwith elastophagocytosis.20 In immunoreactivitystudies of patients with MDE, many have shownthat elastin, but not fibrillin-1, immunoreactivity isreduced in lesional skin.18,19,21,22 The phagocyticactivity against elastic fibers appears then to bedirected against the elastin component and not thefibrillin component in MDE.

It is also well known that several elastin-derivedpeptides have a biologically active role. For instancethe hexapeptide Val-Gly-Val-Ala-Pro-Gly hasbeen shown to exhibit a chemotactic effect onfibroblasts and monocytes,23 whereas kappa-elastinhas marked biological effects on human polymor-phonuclear leurkocytes.24 However, it is notknown whether they specifically triggerelastophagocytosis.

Sun exposure and elastophagocytosisAlthough many studies have shown changes and

degradation in elastic tissue from sun exposure,25-28

the role of sun exposure in triggering elastophago-cytosis is still unclear. There is only circumstantialevidence linking sun exposure and elastophagocy-tosis. For instance, Abbas et al29 demonstratedelastophagocytosis in 5 cases of extragenital lichensclerosus, 4 of which were on sun-exposed areas.

Patroi et al18 suggested that ultraviolet radiationexposure induced MMP-9 expression by fibroblast-like cells that in turn could lead to elastic fiberdegeneration in MDE. In addition, in a study on 21granuloma annulare (GA) cases on sun-exposedskin, elastophagocytosis and elastic fiber loss wasnoted in all cases.1 However, elastophagocytosis is

not indubitably directedagainst sun-damaged elasticfibers as it has beendescribed in several entitiesthat are not always associ-ated with sun expo-sure.2,21,30-32 This possiblyindicates that sun exposureis not the only factor leadingto elastophagocytosis butthat there are other environ-mental and host factors thatmay play a role in its etiopa-thogenesis. In conceptual-izing elastophagocytosis, wecan distinguish: a substrate,

in this case elastic fibers, and an action (phagocy-tosis) carried out by an effecter cell brought on by 1or several triggers leading to elastic fiber loss andexpression of a specific disease (Fig 3).

ENTITIES CONSISTENTLY EXHIBITINGELASTOPHAGOCYTOSISMid-dermal elastolysis

Although many question its existence as adistinct entity, MDE is generally considered to bean acquired disorder of elastic tissue characterizedon histology by selective mid-dermal loss of retic-ular elastic fibers. In 50% of cases, lesions arepreceded by erythema, burning, and urticarialplaques that resolve, leaving a well-demarcatedpatch of fine wrinkling.21 Three types of MDEhave been described: type I (classic type) ischaracterized by well-demarcated patches of finewrinkling; type II features perifollicular papularprotrusions with elastic tissue loss; and type III ischaracterized by reticular erythema andwrinkling.21

In a study of 79 MDE cases, elastophagocytosiswas reported in 29.1% of cases.21 On electronmicroscopy, elastophagocytosis was identified evenwhen it is not always evident on light micro-scopy.7,8,33 It was observed that inflammation degreeon histology parallels the presence of multinucleatedgiant cells and elastophagocytosis, and this is linkedto lesion age: the earlier the biopsy, the more likely itis to find elastophagocytosis.18 In addition, it appearsfrom several reports on type III MDE that focal

Table I. Differential diagnosis of cutaneous lesions with elastophagocytosis

Entities exhibiting elastophagocytosis on microscopy

Entities consistently exhibiting

elastophagocytosis

Entities inconsistently

exhibiting elastophagocytosis

Entities rarely exhibiting

elastophagocytosis

Elastolytic disorders Inflammatory Elastolytic disordersMid-dermal elastolysis GA AnetodermaPapillary-dermal elastolysis LS Acquired cutis laxa

Sarcoidosis PXEInflammatory Linear elastosisActinic granuloma Neoplastic

GMF InflammatoryNeoplastic NXGGranulomatous slack skin Neoplastic Sweet

AFX Morphea

InfectionsCutaneous leishmaniasisBlastomycosisLeprosy

NeoplasticEruptive vellus cystDFKABCC

Medications (CSF, nicorandil)

AFX, Atypical fibroxanthoma; BCC, basal cell carcinoma; CSF, colony-stimulating factor; DF, dermatofibroma; GA, granuloma annulare; GMF,

granulomatous mycosis fungoides; KA, keratoacanthoma; LS, lichen sclerosis; NXG, necrobiotic xanthogranuloma; PXE, pseudoxanthoma

elasticum.

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elastophagocytosis is more frequently observed withmost instances showing the presence of inflamma-tion on histology.34-40

Similar to MDE, Hashimoto and Tye9 describedthe sole case of papillary-dermal elastolysis, which ischaracterized by complete loss of papillary-dermalelastin with elastophagocytosis.

Annular elastolytic giant cell granulomaFirst proposed by Hanke et al,41 the term ‘‘annular

elastolytic giant cell granuloma’’ was proposed forcutaneous annular lesions with the histologic back-ground of multinucleated giant cell infiltrate, elastol-ysis, and elastophagocytosis localized mainly in themid dermis (Fig 4). Thus, AEGCG includes actinicgranuloma, which shares similar clinical and histo-pathological features.6,42 Although some investiga-tors maintain that AEGCG is a variant of GA, manyothers believe that the absence of connective tissuenecrobiosis and the quantitatively dominant elastictissue changes microscopically distinguish AEGCGfrom GA.43 Consequently, although elastophagocy-tosis is a consistent feature of AEGCG detected inevery case, it is not as common in GA cases.42-46

Other microscopic features of AEGCG include a

granulomatous component consisting of multinucle-ated giant cells typically distributed peripherally to acentral zone that lacks elastic tissue. The granulo-matous area often contains fragmented elastic fiberswith easily identifiable elastophagocytosis. A pali-sading arrangement of histiocytes is usually not afeature. Typical solar elastosis in the surroundingtissue is not a consistent feature.42

Granulomatous slack skin diseaseGranulomatous slack skin (GSS), unlike granulo-

matous mycosis fungoides (GMF), is currently recog-nized as a distinct rare variant of mycosis fungoides(MF).47-50 It usually presents initially as asymptomatic,erythematous papules and plaques that progress,with elastic tissue loss, to boggy pendulous folds ofredundant skin commonly on inguinal and axillaryregions of Caucasian men in their third to fifthdecades of life.47-50 Lesions may grow de novo orless commonly manifest within a background ofpatch- or plaque-stage MF. Classic histologic featuresinclude dense diffuse dermal infiltrate of atypical,irregular, and convoluted lymphocytes that mayextend to the subcutaneous tissue (Fig 5).Numerous histiocytes and multinucleate giant cells

Fig 1. Elastophagocytosis: phagocytosis of elasticfibers that microscopically appear in the cytoplasm ofhistiocytes, multinucleated giant cells, or both. (Hematox-ylin-eosin stain; original magnification: 340. Inset,Verhoeff-van Gieson stain; original magnification: 340.)

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are present diffusely in the dermis and display prom-inent elastophagocytosis and lymphophagocytosis.Loss of elastic fibers is a universal finding in GSS andusually correlates with the extent of the granuloma-tous infiltrate. Elastophagocytosis is a very consistentfeature that has been described in more than half ofthe cases reported and usually contributes to thewidespread dermal elastic tissue loss. An ultrastruc-tural study showed that the majority of the elasticfibers that undergo elastophagocytosis in GSS weremorphologically abnormal or degenerated, and werein contact with multinucleate giant cells by coatedvesicles.50 Based on these results, it seems thatmultinucleated giant cells actively phagocytoseddegenerated elastic fibers by receptor-mediated pino-cytosis. Noncaseating granulomas may even benoted. Epidermotropism andPautrier microabscessesmay be present but are not commonly prominent.

ENTITIES INCONSISTENTLY EXHIBITINGELASTOPHAGOCYTOSISGranuloma annulare

Histologically, GA is essentially characterized byeither a palisading granulomatous pattern (granu-lomas surrounding areas of degenerated collagen) orinterstitial granulomatous pattern with increasedmucin deposition (Fig 6). The presence of elasto-phagocytosis in GA varied in different studies. In 1study,31 18 of 50 (36%) GA cases exhibited elasto-phagocytosis, including 11 of 13 (84.6%) generalizedGA cases. In another study of localized GA, 6 of 32(18.75%) cases exhibited elastophagocytosis. As pre-viously mentioned, Ragaz and Ackerman1 reported21 GA cases on sun-exposed skin exhibiting elasto-phagocytosis. Hanna et al44 reported elastophago-cytosis in 2 of 10 (20%) cases whereas it was seen in 4of 10 cases on electron microscopy. In another study

on 38 GA biopsy specimens, elastic tissue changeswere noted in 100% of cases whereas only 2exhibited elastophagocytosis.2 On the other hand,elastophagocytosis was not described in 2 largeseries comprising together more than 400 biopsyspecimens of GA.45,46

Granulomatous MFGMF is a rare histopathological MF variant that

shares overlapping histologic features with GSS(Fig 7) and differs only clinically from it by thedevelopment of bulky skin folds in GSS.48,49,51

Histologically, prominent granulomatous compo-nent may obscure the atypical lymphoid infiltrate inGMF leading to delayed diagnosis. Epidermotropiclymphocytesmaynot always beprominent. Althoughnot as prominent as GSS, elastic fiber changes andelastophagocytosis may also be encountered inGMF.48,49,51 In a recent study, although multinucle-ated giant cells were seen in 22 of 27 GMF biopsyspecimens, elastophagocytosis was only present in5.51 In another study, although elastic fiber loss wasobserved in all 12 GMF cases, only 1 (8%) demon-strated elastophagocytosis.49 In both GMF and GSS,the cytokines released by neoplastic T cellsmay cause activation of histiocytes with subsequentelastolysis and elastophagocytosis.48

SarcoidosisHistologically, sarcoidosis classically exhibits

naked sarcoidal granulomas.52 However, additionalhistologic findings including elastophagocytosis maybe seen. In a study by Ball et al52 the authorsreviewed 28 biopsy specimens of sarcoidosis andnoted elastophagocytosis in 11 (39%) cases with noassociated solar elastosis.

Lichen sclerosusElastophagocytosis has recently been described in

7 of 35 (20%) cases of lichen sclerosis, all of whichwere extragenital.29 Moreover 4 of the 5 cases werelocated on sun-exposed skin. Elastophagocytosismay thus be contributing to the elastic fiber lossclassically seen in the dermal homogenized zone oflichen sclerosis, which may also be mediated byother factors such as inflammatory cell-mediatedelastase enzymatic digestion.

Atypical fibroxanthomaAtypical fibroxanthoma is a rare cutaneous

neoplasm that primarily occurs in older individualson sun-exposed skin. Histopathologically, thisnonencapsulated dermal tumor is composed oflarge, spindle-shaped and anaplastic cells arrangedin fascicles. Elastophagocytosis has been shown to

Fig 2. Scenarios explaining the phagocytosis of ultrastructurally normal elastic fibers. Scenario1: Activated macrophages phagocytose ultrastructurally normal elastic fibers leading to theirdegradation. Scenario 2: Secondary alteration of ultrastructurally normal elastic fibers leading toactivation of macrophages and elastophagocytosis. Scenario 3: Primary alteration of elasticfibers leading to activation of macrophages and elastophagocytosis. UV, Ultraviolet.

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occur more frequently in association with the in-flammatory infiltrate surrounding this tumor whencompared with other epithelial neoplasms.3 In fact adermal granulomatous inflammation was seen in 7 of9 atypical fibroxanthoma biopsy specimens of which5 exhibited elastophagocytosis.3

ENTITIES RARELY/INCIDENTALLYEXHIBITING ELASTOPHAGOCYTOSISCutaneous infections associated withelastophagocytosis

Probably owing to the granulomatous inflamma-tion associated with some cutaneous infections, andthe ability of neutrophils and several types of micro-organisms to secrete elastases andmodify the dermalelastic fiber network,14 elastophagocytosis has been

associated with numerous infections includingleprosy,53 granulomatous syphilis,1 North-Americanblastomycosis,30 bacterial folliculitis, and cutaneousleishmaniasis.54

Drug-induced elastophagocytosisNicorandil is an antianginal vasodilator that has

been associated with ulcerations of the ocularepithelium, gastrointestinal tract, and skin that may,at times, be life-threatening.55-58 A recent reportdescribes a 78-year-old patient with flexural psoriasiswho developed ulceration while on nicorandil.59 Onbiopsy specimen, 1 of the lesions exhibited an ulcerwith prominent elastophagocytosis in the surround-ing dermis. The ulcers eventually healed spontane-ously after discontinuation of the medication.

Fig 4. Annular elastolytic giant cell granuloma. Dermal granulomatous infiltrate withmultinucleated giant cells, loss of elastic fibers, and elastophagocytosis. A, Note adjacent solarelastosis. (A and B, Hematoxylin-eosin stain; original magnifications: A, 34; B, 340. C and D,Elastic stain; original magnifications: C, 34; D, 340.)

Fig 3. Conceptualizing elastophagocytosis in disease: phagocytosis of elastic fibers, broughton by 1 or several triggers leads to the loss of elastic fibers and the expression of a specificdisease. MMP, Matrix metalloproteinase; UV, ultraviolet.

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Fig 5. Granulomatous slack skin. Dense diffuse dermal infiltrate of atypical convolutedlymphocytes that extend to subcutaneous tissue with epidermotropism. Numerous histiocytesand multinucleate giant cells are present and display prominent elastophagocytosis. (A to D,Hematoxylin-eosin stain; original magnifications: A, 34; B, 310; C and D, 340.)

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Granulocyte colony-stimulating factor is a cyto-kine that stimulates the proliferation and differenti-ation of the granulocytic progenitor cells. Interstitialgranulomatous dermatitis (IGD) has been reportedto occur with granulocyte colony-stimulating factortreatment and elastophagocytosis was noted in 3cases of granulocyte colony-stimulating factoreas-sociated IGD.60,61 The authors postulate that

elastophagocytosis is more likely to be linked tothe IGD that to the drug itself.61

Penicillamine is a copper chelator used in thetreatment of Wilson disease. At high doses, it has theability to distort elastic fibers leading topenicillamine-associated dermopathies.62 In 1 casereport, a 36-year-old man with Wilson disease onhigh-dose penicillamine developed lesions of

Fig 7. Granulomatous mycosis fungoides. Dense diffuse dermal infiltrate of atypicallymphocytes with epidermotropism and scattered histiocytes and multinucleate giant cellswith some displaying elastophagocytosis. (A to D, Hematoxylin-eosin stain; original magni-fications: A, 34; B, 310; C, 320; D, 340.)

Fig 6. Granuloma annulare. Focal elastophagocytosis. (A and B, Hematoxylin-eosin stain;original magnifications: A, 34; B, 340.)

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elastosis perforans serpiginosa and cutis laxaconcomitantly. A biopsy specimen taken for a lesionon his arm showed a perforated epidermis withelastophagocytosis.63

Tumor-associated elastophagocytosisRarely, epithelial tumors have been reported to be

associated with elastophagocytosis including

dermatofibroma, keratoacanthoma, and basal cellcarcinoma.3,64

Elastic tissue diseases and elastophagocytosisAnetoderma is an acquired disease of elastic tissue

characterized clinically by small atrophic papulesthat herniate readily into the skin and microscopi-cally exhibit loss of dermal elastic tissue.

Fig 8. Pseudoxanthoma elasticum. Fragmentation and calcification of elastic fibers withelastophagocytosis. (A and B, Hematoxylin-eosin stain; original magnifications: A,34; B,340.C, Verhoeff-van Gieson stain; original magnification: 34. D, von Kossa stain; originalmagnification: 34.)

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Elastophagocytosis has been reported in 2 cases ofprimary anetoderma, 1 of which exhibited markedinflammation.65,66

Acquired cutis laxa is a rare disease resulting fromelastic tissue loss that leads to saggy skin falling intoredundant folds. Histopathologically, it occurs in 4stages.67 Stage I is characterized by the fragmentationof elastic tissue; stage II by the occurrence of alymphoneutrophilic infiltrate; stage III by the pres-ence of elastophagocytosis; and stage IV by elastictissue loss.67 Elastic fiber loss, which may even occursystemically, may thus occur secondary to multiplefactors including elastophagocytosis or even elas-tases produced by inflammatory cells.67 Acquiredcutis laxa was recently reported to occur with IGD ina patient with IgG Lambda monoclonal gammop-athy.68 Rare giant cells with elastophagocytosis werenoted on biopsy specimen.

Pseudoxanthoma elasticum is a rare inheritedelastic tissue disease characterized on histology bythe fragmentation and calcification of elastic fiberswithin the dermis (Fig 8). Elastophagocytosis israrely noted with 1 case report mentioning thepresence of this phenomenon on biopsy specimen.69

Linear focal elastosis is a rare disorder usuallycharacterized by asymptomatic firm, linear,

yellowish, horizontal, parallel streaks commonlyoccurring bilaterally on the lumbar area of predom-inantly Caucasian elderly men. Histologically, itusually exhibits increased dermal elastic fibers thatmay be thinned, wavy, and more or less curled andfragmented. Elastophagocytosis has been describedin 1 case report.70,71

Miscellaneous conditions associated withelastophagocytosis

There is to date, 1 report mentioning the presenceof elastophagocytosis in resolving Sweet syn-drome.15 The authors postulated that this may be aresult of elastase release by neutrophils leading toelastic tissue distortion and elastophagocytosis.

Elastophagocytosis was also noted in a patientwith monoclonal gammopathy of unknown signifi-cance who developed atypical necrobiotic xanthog-ranuloma over her limbs.72 On biopsy specimen,extensive nonpalisading granulomas with multiplemultinucleated giant cells could be appreciatedengulfing elastic fibers.

Other conditions that havebeendescribed to rarelyexhibit elastophagocytosis are morphea,30 eruptivevellus hair cysts,30 and ruptured follicular cysts.1

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ConclusionAlthough elastophagocytosis may represent a

nonspecific incidental process seen in various dis-eases, this phenomenon appears to be a character-istic reproducible feature of distinctive entities suchas MDE, AEGCG, or GSS, and may thus serve as ahelpful clue to their diagnosis. As for etiopatho-genesis, elastophagocytosis may result from diverseinitiating events that reveal the antigenicity of elasticfibers and trigger a cascade of events that lead to acellular immune response and eventually phagocy-tosis of elastin. However, there are still manyquestions that remain unanswered and need furtherclarification in future studies: what triggers thephagocytosis of normal and abnormal elastic tissue?What is the role of ultraviolet light? What are theintrinsic factors that render elastin antigenic?

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