Analysis of Cutaneous Foreign Bodies CHRISTINE JAWORSKY, MD

iscovery and identification of exogenous foreign matter in the skin requires not only a deliberate search, but the appropriate use of available analytic techniques. By correlating cutaneous changes with historical information of antecedent trauma, therapeutic interventions, occupational hazards, and recreational activities, a preliminary list of possible inciting agents forms. At this juncture radiologic studies, light microscopic examination, and ultrastructural analysis are helpful in identifying the nature of foreign material. These techniques will be individually discussed, followed by an in-depth analysis of their application to various types of foreign bodies.

D

Radiographic Studies X-rays and photographic film often permit detection of foreign matter in the skin. The utility of this means of diagnosis depends on the composition, size, and orientation of foreign bodies in tissues.’ Plain radiographs allow detection of materials with radiopacities different from the surrounding soft tissues; thus, highly radiopaque bullet fragments, surgical clips, and metallic fragments are easily identified. Less radiopaque foreign bodies such as glass, aluminum, gravel, and some plastics are less obvious, but they are still visible on plain films.2 Wood splinters, interestingly, are frequently visible on plain radiographs within 48 hours of implantation; they then absorb body fluids and their density becomes similar to surrounding body tissues and can no longer be appreciated on X-ray. l If, however, splinters are coated with lead paint, they remain visible after 48 hours have elapsed.3*4 In terms of size, the object to be visualized by

X-rays must be larger than the resolution capability of the screen-film combination, which is a function of the type of film and penetrability of the X-ray beam. Small, highly radiopaque objects, such as metallic particles, are more easily discernable than less radiopaque objects of similar size, such as fragments of glass. Finally, location may limit detection if foreign matter is lodged over bony structures, thus rendering it invisible because of background, In such instances obtaining two films at right angles to each other will obviate this problem. Xeroradiography can detect some foreign objects not easily seen on radiographs by enhancing contrast between objects and adjacent soft tissues, the so-called edge effect.5 Objects visualized by this means include thorns, sea urchin spines, plastic, rubber, and graphite.6*7 Xeroradiographs are less widely available than plain radiographs, more costly, and require approximately nine times the dose of radiation of routine radiography to obtain an image.s Although ultrasound and computed tomography have also been used to detect the presence of foreign matter, and magnetic resonance imaging may have potential application, these methods are less available and more costly. Thus, although more refined imaging techniques can be of potential diagnostic assistance, plain radiographs remain the most useful, widely available, and cost-effective means of screening soft tissues for foreign bodies. Radiologic studies in dermatology have traced the cause of localized argyria to silver acupuncture needles implanted in the skin more than 10 years prior to skin changes,9J0 and aroused suspicion of narcotic addiction by discovering broken needle tips in soft tissues3

_

Light Microscopy

From the Department @Dermatology, Universify ofPennsylvania, Philadelphia, Pennsylvania. Address correspondence to: Christine jaworsky, M.D., Department of Dermatology, University of Pennsylvania, 2 Maloney, 3600 Spruce Street, Philadelphia, PA 19204.

As particle size diminishes, magnification by microscopy becomes necessary for detection of foreign materials. Tissue of the affected area is sampled, fixed (most often in formalin), processed, and stained. Implanted materials

0 1991 by Elsevier Science Publishing

Co., Inc.

l

0738-081x/91/$3.50

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Clinics in Dermatology

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evoke host responses that vary according to their inherent physical, chemical, and infectious properties. When obscured by brisk inflammatory infiltrates, foreign materials can be unmasked by employing special stains or by manipulating light entry into the microscope. A particularly useful stain is the periodic acid-Schiff stain, which reacts with adjacent hydroxyl groups of 1,2 glycols in polysaccharide molecular structures and thus highlights splinters, talc, starch, and fungi in tissues.” Two ways of manipulating light entry are darkfield illumination and polaroscopy. Darkfield illumination prevents light from directly entering the objective and diffracts light so that small particles or fine lines appear as bright stars on a dark background. Using this technique metallic substances such as gold and silver can be more easily perceived. Polarization microscopy is light microscopy modified by the use of two specifically constructed prisms or lenses. One lens, placed below the specimen, produces a light beam whose rays vibrate in only in one direction; the other, placed above the specimen, analyzes the rays emanating from the specimen. Crystalline substances or objects with a high degree of molecular organization rotate polarized light and become visible as bright objects on a dark background. Such objects have the property of birefringence and include silica, talc, suture material, wood, and plant matter.12 The limit of resolution of a light microscope equipped with an oil immersion lens, giving a maximum magnification of 1200 times, is 0.25 micrometers (2500 Angstroms).13 Light microscopy is similar to roentgenologic examination in that it is an excellent screening tool that aids localization of the offending material. Definitive identification of such material, however, depends on whether or not it has a characteristic appearance in tissues. Sutures, for example, are easily identified with microscopy. By contrast, dermal pigment deposition is the histologic change of chrysiasis, argyria, minocycline pigmentation, and tattoos. Whereas light microscopy confirms the presence of pigment, it cannot always distinguish its cause. In such instances, ultrastructural analysis may assist in arriving at a definitive diagnosis.

Ultrastructural Analysis Electron microscopy is a versatile tool in which a beam of high-energy electrons bombards tissue sections. It is useful in scanning and transmission modes for foreign body analysis. Scanning electron microscopy (SEM) visualizes the surface of tissue and is thus useful in locating foreign material not uniformly dispersed in tissue. With bombardment, electrons scattered from the surface of the specimen can be analyzed by Backscattered Electron Imaging (BEI), a system that permits detection of particles

as small as 500 Angstroms in diameter.14 In transmission electron microscopy (TEM) electrons penetrate tissue and visualize the internal structure of a specimen. The direct impact of a beam of electrons focused onto a one-micrometer or less diameter spot (the probe), causes characteristic X-rays to be emitted from the specimen, which can then be analyzed with electron dispersive X-ray analysis (EDXA). This system, also known as electron probe microanalysis, is able to locate and identify foreign materials in skin and other organs in quantities as small as lo-l6 grams or 100 parts per million.15 In addition, as electrons pass through the specimen, they lose energy, which can be detected and analyzed by another system known as Electron Energy Loss Spectroscopy (EELS). With EELS elements of molecular weights lower than those identified by EDXA can be discerned.16 For a schematic representation of EDXA and EELS, see Figure 1. Either freeze-dried cryosections or paraffin-embedded thin sections may be used for analysis of inorganic particulates or insoluble tightly bound exogenous metals.*6-19 For example, sections of 5 - lo-pm paraffin-embedded tissue may be placed onto spectroscopically pure ultrasmooth carbon planchets, deparaffinized, and coated with carbon by vapor deposition to minimize charging of the specimen by the electron beam. For sections thinner than 5 pm, the last step may be omitted. Occasionally, when light microscopy has been necessary to locate the particles prior to analysis, sections have been successfully lifted off the glass slide and placed onto a carbon planchet for analysis.20 The above-described sophisticated analytic techniques have several limitations. First, EDXA has a low collection efficiency for elements of low anatomic number. For example, lo4 atoms of sodium must be ionized for each X-ray detected. l7 Second, there is some overlap in spectral

Figure 1. Schematic representation of electron dispersive X-ray analysis and electron energy loss spectroscopy. Analytic

Transmission

Electron

Microscopy

Clinics in Dermatology 1991;9:157-178

JAWORSKY ANALYSIS

emissions of transitional elements with the element of preceding anatomic number.” New computer software has partially obviated this problem by allowing better separation of spectral peaks. Third, spectral interference can occur from artifacts such as mercurial fixatives from Zenker’s formalin, aluminum from hematoxylin, or other exogenous contaminants. These must be excluded as background to avoid erroneous interpretation.16 Finally, because EDXA and EELS detect the presence of elements, they provide data regarding chemical composition only. If information on mineral crystals is necessary, selected area electron diffraction (SAED) is an appropriate analytic technique. As with EDXA and EELS, TEM is used in SAED to direct an electron beam at the individual particles or selected sites of large particles. The resulting diffraction patterns are characteristic and allow, for example, identification of specific types of asbestos fibers.16 The disadvantages of SAED are complex and tedious specimen preparation, the necessity of proper crystal orientation, and prolonged examination times for data acquisition of a given sample.i6 Other examination techniques (Table 1) such as laser microprobe mass analysis (LAMMA), proton/particle induced X-ray emission (PIXE), and proton microprobe (PMP) have been used for applications similar to EDXA, and differ in that LAMMA requires a laser beam source, whereas PIXE and PMP require a proton accelerator.21 PMP offers greater sensitivity (Cl0 ppm) than EDXA (> 100-200 ppm) because the background is very low due to the stopping power of the specimenz2 Neutron activation analysis is also a sensitive technique that detects as little as 5 parts per million of mercury in tissue. This method, however, requires access to a nuclear reac-

OF CUTANEOUS

FOREIGN

tor.23 A recent addition to available analytic techniques is X-ray microscopy, which uses X-radiation for chemical analysis. X-ray microscopes can achieve a magnification of 100- 1000 diameters and a resolution of approximately 0.25 micrometers. They identify elements in amounts of lo- l2 to lo-” grams without placement of the specimen in a vacuum, as is necessary in electron microscopy.24 These latter analytic methods are currently less available than EDXA. To summarize, in instances where analysis of elements present in the skin is necessary, electron microscopy with BEI, EDXA and EELS allows structural and elemental analysis of skin biopsies. BE1 is used in conjunction with SEM. TEM with EDXA can detect and measure most elements of anatomic number greater than beryllium, while TEM with EELS can detect and measure elements lighter than sodium.16 These analytic techniques are available in universities and industries equipped with electron microscopes.

Applications The setting in which foreign materials are acquired, ie, iatrogenic, cosmetic, traumatic, occupational, and selfinflicted, may indicate the types of substances to be found. Summaries of each follow, and the accompanying tables provide additional information.

Iatrogenically Acquired Foreign Bodies Therapeutic agents that produce detectable skin changes include metallic and non-metallic drugs, and surgically introduced materials (Table 2). Medications often cause

Table 1. Microanalytic Techniques Probe

Source

Analytic Method

Electron

Electron microscope

Backscattered Electron Imaging (BEI) Electron Dispersive X-ray Analysis (EDXA)

Proton

Proton accelerator

Neutron Laser

Nuclear reactor Laser beam

X-ray

X-ray microscope

159

BODIES

Electron Energy Loss Spectroscopy (EELS) Proton Induced X-ray Emission (PIXE) Proton Microprobe (PMP) Neutron activation analysis Laser Microprobe Mass Analysis (LAMMA) X-ray microscopy

Sensitivity/Limitations 500 B particle diameter lo-i6 grams or 100 parts per million Elements of molecular weight >Na Elements of molecular weight Aluminum 10 parts per million 5 parts per million Parts per million; parts per billion destructive to sample lo-I2 to lo-” grams; no vacuum necessary

injection site

asymptomatic solitary mass

Polyvinylpyrrolidine (now banned in USA)

Anti-arrythmic34~35

Oral Medications sun-exposed sites; granules in cornea

vaccination sites

erythematous nodules

Adsorbed Diphtheria Tetanus Pertussis

slate-grey skin

injection sites of hypertrophic scars, keloids, cysts

papules or nodules, may have erythema

Intralesional steroids

AntiinflammatoqP

amiodarone

injection sites

fun.mcle-like sterile lesions

Zinc-containing insulin

Anti-Diabeti?

Plasma Expander/ Injection Retardant97,98

sun-exposed areas, spares creases; cornea1 granules

Distribution

slate-grey, blue violet skin

Medications

Change

Clinical

Gold compounds (chrysiasis)

Iniectable

Table 2. latrogenic Foreign Bodies

yellow-brown granules of various sizes

fibrosis, lymphoid infiltrate; +/germinal centers blue-grey material; alcoholic congo red +

perivascular, upper dermis

macrophages

variable histiocytic & giant cell response in reticular dermis to subcutis deep dermis

tightly-staining pools of granular amorphous acellular material

in

early: neutrophils around crystals; late: fibrosis

rhomboldal crystals (early only)

in macrophages and superficial dermal vessel endothelial cells

Location

irregular large black granules

Change

NR

NR

NR

NR

early: + late: -

NR

Polariscopy

Light Microscopy

NR

NR

NR

NR

NR NR

+

Darkfield

l -2firn myelinlike or lamellar bodies with l2A periodicity in endothehal cells & pericytes

histiocytic vacuoles & ovoid lamellar structures

membranebound ED linear material in histiocytes

NR

membranebound ED angulated particles in endothelial cells and macrophages NR

Electron Microscopy

EDXA: iodine peak

spectropho-

peak

EDXA aluminum

percutaneous zinc sulfate injection reproduced lesions; EDXA wilt detect zinc none reported; clinicopathologic correlation

EDXA: gold peak on emission spectrum

Diagnostic Study

Medications

Antiseptic Ointment103

Topical

titaniumcontaining

imipramine

pearly-yellow discrete & coalescent papules sites of application

brown, variablysized granules

golden-brown pigment

sun-exposed sites iris color change

slate-grey

upper dermis, rarely in maaophages, around capillaries

superficial dermis: intra& extracellular

golden-brown granules

sun-exposed skin; lenticular opacities

dermis & subcutis in macrophages andmarim around fat globules superfical dermis in perivascular macrophages, endothelial & Schwann cells

yellow-brown pigment in unstained sections

yellow to dark brown pigment

slate-grey, metallic bluish

early: red (l-4 wks.) late: brown-black

clofazimine

to

intra- & extracellular in dermis intra- & extracellular especially deep dermal

brown-black granules

in scars & areas of inflammation diffuse, increased in sun-exposed sites cornea1 deposits primarily lesional, also diffuse

3. blue-black

yellow-brown grey skin

epidermis & upper dermis; intracellular pigment in dermis & subcutis

brown-black granules brown-black granules

diffuse & sunexposed normal skin of arms & legs

1, “muddy color” 2. blue-grey

chloroquine

minocycline

Psychotropic37~‘o’~‘o* chlorpromazine

LeprostatiP

Antibiotic”’

-

-

+

+

NR

NR

NR

NR

+

+

NR

NR

-

-

NR

EDXA: titanium peak

none yet

spectrophotometry; may see red refractile crystals on H&E EDW sulfur peak in inclusions

none yet

raphy NR

=gh performance liquid chromatog-

NR

Table 2 continued on following page

SOO-6OOnm rounded ED particles, extracellular &in macrophages; free or in membranebound lysosomes

variably-ED membranebound inclusions in same cells as light microscopy +/- melanin homogenous ED variably-sized granules in fibroblasts, histiocytes; also perivascular

NR

NR

ED particles +/- iron, in maaophages with/without membrane NR

NR

acellular

elongate crystals

crystals with Maltese cross configuration

sites of previous surgery

sites of previous surgery

sites of previous surgery

erythematous nodules

red-brown papules

erythema with induration

absorbable gelatin

talc (also Table V)

starch

Hemostatics

dermis 8 subcutis: mixed neutrophilic granulomatous infiltrate dermis &/or subcutis granulomatous infiltrate nodular granulomatous infiltrate with giant cells around crystals granulomatous infiltrate with giant cells

Location

&

+

+

variably

+

Polariscopy

Light Microscopy

NR

NR

-

NR

Darkfield

(+) = posifive; (-) = negative; (+,I-) = with or without; NR = not reported; ED = electron dense; EDXA = electron dispersive X-ray nnalysis; PAS = periodic acid Schlif

material

ovoid, acellular material

sites of previous surgery

Change

erythematous nodules

Distribution

various materials

Materials

Change

Clinical

Suture

Surgically-Zmplanted

Table 2. latrogenic Foreign Bodies (continued)

NR

NR

NR

Electron Microscopy

H&E

PAS + crystals with Maltese cross configuration on polariscopy

EDXA

H&E appearance

+/polariscopy

routine

Diagnostic Study

Clinics in Dermatology 1992;9:157-178 skin discoloration by deposition of parent drugs or metabolites in the dermis, with or without associated collections of hemosiderin. In addition, inherent photoreactivity of parent compounds or their metabolites may cause or enhance cutaneous hyperpigmentation. A notable example in which both mechanisms play a role is chrysiasis. This is a conspicuous hyperpigmentation of varied hues on the sun-exposed surfaces of patients with rheumatoid arthritis who have received large doses of parenteral gold therapy in the form of either gold sodium thiomalate or aurothioglucose. Chrysiasis has been reported with greatest frequency in patients who have received in excess of 55 mg/kg of elemental gold, and thus appears to be dose dependent.25 The peculiar slate-grey, grayish purple, grayish-blue, bluish-violet, blue-green, or brownish-yellow hyperpigmentation is induced by exposure to sunlight, and can be reproduced in sun-shielded sites by exposure to ultraviolet light.26 Although the most characteristic findings of chrysiasis occur in the skin, clinically asymptomatic ocular deposits occur as well; these may be detected by slit lamp examination as minute glittering yellow-brown to violet deposits distributed over the entire cornea.27 Cutaneous histologic findings are pigment granules around superficial dermal vessels and in macrophages between collagen bundles.25 Ultrastructurally, gold particles are found in endothelial cells and macrophages in membrane-bound structures associated with melanosomes.28 In chrysiasis, as in heavy metal-induced hyperpigmentation of mercury, silver, bismuth, and arsenic, cutaneous discoloration is thought to be due to dermal metallic deposits. Increased melanin production has been a variable finding.29*30 The study of most diagnostic utility in identifying the nature of the pigment granules is EDXA, which demonstrates a spectrum consistent with the presence of gold.25 Therapeutic agents complexed with metallic ions may cause cutaneous alterations other than hyperpigmentation. Two examples are aluminum and zinc-related granulomas. Aluminum-induced granulomas have been noted l-2 years after injection of adsorbed diphtheria, tetanus, and pertussis vaccine.31 With light microscopy, involved sites show deep dermal fibrosis that may involve the subcutis accompanied by occasional giant cells and lymphoid aggregates containing germinal centers. Ultrastructural studies have shown membrane-bound electron-dense linear material in histiocytes. Definitive identification of aluminum within these structures, however, requires X-ray microanalysis. Similarly, zinc has been identified as a cause of cutaneous granulomas occurring with insulin therapy. 32 Sterile furuncle-like lesions occur at insulin injection sites and eventually resolve with atrophic scars. Routine histology shows neutrophilic infiltrates surrounding rhombohedral crystals that are bril-

JAWORSKY ANALYSIS OF CUTANEOUS FOREIGN BODIES

163

liantly refractile on polaroscopy in early lesions (3 days old). At 1 month lesions show granulomatous infiltrates with fibrosis and absence of crystals. Although EDXA was not used in the case reported, identical lesions were reproduced with intralesional injection of zinc sulfate.32 Among non-metallic drugs, the antiarrythmic amiodarone causes a slate-grey discoloration of sun-exposed skin. In the eyes, cornea1 yellow-brown stippling (verticiliate keratopathy) symptomatically produces halos around objects, which resolves with discontinuation of therapy. 33 B y light microscopy, similar yellow-brown refractile granules are seen in the reticular dermis. These were thought initially to represent lipofuscin. Ultrastructurally, however, they correspond to concentrically arranged intralysosomal inclusions in endothelial cells, pericytes, and macrophages, similar to deposits associated with chloroquine therapy and with Fabry’s disease.34 With EDXA these inclusions have been found to contain iodine, a major component of both amiodarone and its major metabolite, desethylamiodarone.34,35 Thus, iodine bound with lipofuscin in secondary lysosomes probably reflects macrophage phagocytosis of degraded cell membranes bound to lipid-soluble amiodarone.35 Although much analytic information in detecting metallic and non-metallic drugs in the skin has been gained through EDXA, this technique cannot provide diagnostic assistance when drugs do not possess a metallic or characteristic element in their structures. For example, chlorpromazine has long been known to induce cutaneous discoloration with prolonged high-dose therapy. Early reports of chlorpromazine hyperpigmentation suggested the cause of discoloration to be increased local epidermal melanin and dermal melanin deposition;36 a recent study with EDXA indicates the presence of sulfur, a component of the parent drug. This data suggests that chlorpromazine or its metabolite is present within the golden-brown pigment granules of dermal histiocytes and pericytes.37 Another example is the tetracycline derivative, minocycline. This drug has been noted to produce three types of discoloration: (1) a background “muddy” appearance to normal skin;38,39 (2) blue-grey hyperpigmentation of normal sun-exposed skin;40,41 (Figure 1); and (3) bluegrey hyperpigmentation within scars or areas of previous inflammation.42,43 Nail and tooth discoloration have also been reported. By light microscopy pigment deposition has been observed at various levels in the dermis, with variable staining for iron and melanin. Ultrastructural studies have shown free and membrane-bound bodies with variable iron content (see Table 1). Although EDXA identified the presence of iron, calcium, sulfur, and chlorine, high-performance liquid chromatography was necessary to identify minocycline in extracts of lesional pigmented skin.44

164

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JAWORSKY

In contrast to the minute deposits of medicaments in skin, surgically implanted materials are generally larger and have characteristic morphologic appearances. Two such examples are suture materials (Figure 2) and hemostatic agents (Figure 3). The acellular nature of these materials, characteristic geometric shapes, and surrounding inflammatory infiltrates admixed with giant cells allow their identification with relative ease in routine histologic preparations. In addition, because of internal organization, suture material is frequently recognizable by its refractility on polariscopic examination. Thus, among therapeutically-acquired foreign bodies, deposits of various drugs in the skin are diagnostically most challenging. Morphologic studies alone are frequently inadequate for definitive identification of these compounds. EDXA has proven extremely useful in many, but not all such cases.

Cosmetically Acquired Foreign Bodies Cosmetic agents that induce cutaneous alterations can be grouped into those injected percutaneously and those applied topically (Table 3). Tattoos are easily diagnosed by clinical and histologic appearance (Figure 4), and reactions to injected oily substances are characteristic because of their dermal “Swiss cheese” pattern (Figure 5).45 By contrast, reactions to silicone (polydimethylsiloxane) can

Figure 3. A) Low-power histologic appearance of absorbable gelatin sponge and surrounding fibrosis. B) High-power view of peripheral granulomafous infiltrate composed of many foreign

Figure 2. Highly characteristic microscopic appearance suture in a healing wound. Inset shows bright refracfilify material with polaroscopy.

of of this

be unusual and challenging because silicone can migrate to locations distant from the site of its application. Three forms of silicone are medically used: (1) liquid for soft tissue augmentation by local injection, (2) bag-gel implants for augmentation mammoplasty, and (3) silicone elastomer in joint prostheses.46,47 Local accumulation and migration of all three forms may occur. Xeroradiographs can be helpful in the diagnosis of migratory silicone granulomas: they provide comparisons of radio-

body giant cells and lymphocytes. acellular gelatin sponge.

C) High-power

view of the

Silicone’7

variably-sized cavities giving “Swiss cheese” look

breasts, buttocks, thighs, penis, scrotum, anus

variably-sized cystic spaces

acellular zone surrounded by foreign body reaction

at or distant to injection sites

injection sites

erythema, induration

bovine

Skill

nodules, adenopathy’

plaque-like indurated masses, +/ulceration or sinus tracts

01eogranuloma45~*0~‘09 para& vegetable oils mineral oils

variably-sized intra- & extracellular pigment

anywhere on

Skill

variably-sized intra- & extracellular pigment

Change

anywhere on

Distribution

polydimethylsiloxane

designs with illdefined borders

india ink, shoe polish, paint, ink, pencil lead carbon particles

Amateur

sharplydemarcated colored artistic designs

Change

Clinical

ochre, senna, cobalt chromium, magnesium mercury, cadmium

Decorative Tattoo106J07 Professional

Injected Agents

Table 3. Cosmetic Fore&n Bodies

tissues; variable histiocytic inflammation fibrosis, minimal foreign body response deep dermis & subcutis; may also have diffuse granulomatous reaction with eosinophils & few giant cells

in soft

relatively uniform superficial dermal location; usually minimal inflammation at variable depths of dermis; usually minimal inflammatory infiltrate dermis &/or subcutis, fibrosis & giant cells

Location

(-) contrasts with normal collagen

(adulterants give + exam)

-

NR

NR

NR

Polariscopy

Light Microscopy

NR

NR

NR

NR

NR

Darkfield

type1 collagen antibody

irnmunoperoxidase using anti-bovine

infrared absorption spectroscopy & field desorption mass spectroscopy infrared spectrophotometry or EDXA

H&E appearance

Diagnostic Study

Table 3 continuedon following page

periphery and in crevices of implant without vascularization

rounded intracytoplasmic inclusions with areas of electron lucency & density “resting” fibrocytes at

macrophages dr granules free in dermis NR

membranebound granules in

membranebound granules in macrophages 8.1granules free in dermis

Electron

Microscopy

Agents

upper dermis, surrounded by histiocytes, plasma cells & giant cells

superficial dermis

homogenous golden-brown bananashaped material

infiltrate of histiocytes, lymphocytes & giant cells

sites of application, often face & neck

application sites

reddish-brown or flesh colored papules

zirconium

brown-black granules in linear distribution

hyperpigmentation &/ or colloid milium-like papules

upper dermis, in macrophages & around capillaries

Location

hydroquinone

line to coarse

Change

brown-grey or slate “dirtylooking” skin

face, neck, accentuated in creases and around eyes

Distribution

-

NR

-

Polariscopy

Light Microscopy

mercury

Change

Clinical

l Xeroradiography my detect densities with rounded contours in implant b remote sites (+) = positive; (-) = negative; NR = not reported; ED = electron dense; EDXA = electron dispersive X-my analysis

Lo~onsl13m

Deodorants/

Bleaching creams23S7J 12

Topical

Table 3. Cosmetic Foreign Bodies (continued)

NR

NR

+

Darkfield

ED 140-3400 & rounded particles with jagged edges associated with elastic fibers, & macrophages; also extracellular giant abnormal elastic fibers, appearing as elastotic clusters of ED material in upper dermis NR

Electron Microscopy

detectable with EDXA

none yet

reported with neutron activation analysis; detectable with EDXA

Diagnostic Study

Clinics in Dermatology 1991;9:157-178

JAWORSKY ANALYSIS OF CUTANEOUS FOREIGN BODIES

167

Figure 4. Tattoo. A) Numerous darkly pigmented granules in clumps at various levels of the dermis. B) High power view showing granules in extracellular and intracellular locations.

densities of soft tissue masses in question to densities of known silicone implants. 48 Silicone lymphadenopathy from migration of silicone through lymphatics has been observed most often after traumatic rupture of bag-gel breast implants, and after fragmentation of elastomer joint prostheses with mechanical stress.4g,50 Although hematogenous migration has most often occurred with hemodialysis (tubing)5i and cardiopulmonary bypass procedures (anti-foam agent)T2 injections of large amounts of silicone into soft tissues have resulted in fata-

lities probably because of inadvertent direct intravascular injection.53 Histologically, silicone produces a range of reactions. The elastomer produces a foreign body giant cell reaction in soft tissues and lymph nodes. Silicone liquid and gel, by contrast, cause the formation of variably sized round to oval cystic spaces that retain small droplets of gel or appear empty and are surrounded by relatively few giant cells. If polaroscopy shows birefringent particles, this is likely due to contaminants because silicone is not bire-

Figure 5. Paraffinoma. A) Low power view of the characteristic “Swiss cheese” appearance. B) High power view of the variably-sized cystic cavities surrounded by histiocytes

and lymphocytes. C) High power view of aggregates of multinucleated giant cells forming granulomas. Courtesy of Bernett L. Johnson, Jr., M.D.

168

JAWORSKY

fringent. Despite losses in processing, minute residual amounts of silicone may be detected by scanning EM and identified with EDXA.” a hyperpigmentation proExogenous ochronosis, duced by chronic application of hydroquinone-containing bleaching creams, has recently received much attention. This disorder was initially reported in South African blacks who used 2% or greater concentrations of hydroquinone.54 More recently, however, it has been observed in darkly pigmented individuals outside of South Africa using lesser concentrations of this compound.55,56 Histologically, ochre-colored (hence the name ochronosis), hobanana-shaped material is present as mogenous, clumped aggregates in the upper dermis. Although this finding is reminiscent of endogenous ochronosis, abnormalities of homogentisic acid oxidase as indicated by urine abnormalities or discoloration of connective tissue are absent in individuals using bleaching creams. One ultrastructural study suggests that this unusual pigment change is due to enlarged, irregular, and fragmented elastic fibers, whereas a recent light microscopic study suggests that dermal melanin complexed with hydroquinone causes this change. 57*58Perhaps chemical analyses, and not morphologic observations, would reveal how hydroquinone interacts with the dermal matrix to produce these alterations.

Traumatically Acquired Foreign Bodies A wide array of agents are embedded in the skin as a result of trauma (Table 4). With fibers, local inflammation and discomfort are common sequellae. Wood splinters (Figure 6) occasionally present surprises in that they may carry fungal organisms that may eventuate in phaeomycotic cyst formation. 5g,60Particulate matter, by contrast, may produce cosmetic disfigurement (blast tattoos) or multiple inflammatory papules and nodules (silica). More serious consequences may follow the percutaneous introduction of mercury, most often the result of a broken thermometer. Localized cutaneous masses, acrodynia, and death have all been associated with such a seemingly inconsequential occurrence.61-63 Cases of selfinjection of mercury have been reported as we11.64-66 In either setting, metallic mercury undergoes slow biologic oxidation in tissues to a soluble mercuric salt, which can react with sulfhydryl radicals and thus interfere with many enzyme systems. 67 Clinically, plain X-rays are useful for disclosing the extent of mercury deposits in soft tissues and the lungs. Such deposits appear as radiopaque shadows composed of numerous tiny round dots resembling paint brush stipple. 64 In addition, urinary mercury levels reflect excretion rates, and assist in monitoring therapy with chelating agents.

Clinics in Dermatology 1991;9:157-178

Figure 6. Histologic appearance of a splinter, with its Inset demonstrating its characteristic rectangular cell walls. bright refractility with polaroscopy. If mercury deposits are not clinically suspected, sampling for histologic studies is of diagnostic utility. Metallic mercury in cutaneous granulomas appears as dark grey to black, opaque, variably sized, spherical globules surrounded by collagen necrosis and a periphery of mixed inflammatory cells including foreign body giant cells and granulation tissue. EDXA of sampled tissue provides definitive identification of metallic mercury.” EDXA is also a valuable tool in positively identifying particles of silica in skin and amalgam tattoos in the oral cavity. Silica granulomas are of particular interest because they may appear 6 months to 60 years after traumatic implantation. This latency may be due to slow conversion of silica into colloidal silica.68 The simultaneous occurrence of several lesions, reactions in a low percentage of exposed individuals, and collections of IgG in granulomas suggest that silica granulomas may form on an immunologic basis. 6g,70Histologically, affected areas show confluent non-caseating granulomas with Langhan’s giant cells and occasional asteroid bodies. Polaroscopy reveals birefringent particles associated with giant cells (Figure 7). Although chemical analysis, microincineration, and spectroscopic analysis have been used in the past, ‘l EDXA provides positive identification of silica without destruction of the specimen.“~‘* Amalgam tattoos are of clinical significance in that these pigmented macules may clinically mimic malignant melanoma as they can enlarge and develop ill-defined borders with corrosion.73,74 Amalgam is an alloy composed primarily of mercury combined with silver, tin, and zinc. Because of galvanic activity of these dissimilar metals in physiologic solution, amalgam rapidly loses copper and zinc, and lesser amounts of tin and mercury.73 Remaining silver precipitates with sulfur, which causes the tissue pigmentation.74

Clinics in Dermafology 1991;9:157-178

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Figure 7. Silica granuloma. 4) Low power showing numerous dermal granulomas and intervening lymphocyfic infiltrate. B) High power of epifhelioid granulomas without central necrosis, surrounded by lymphocytes. C) Polaroscopy of the same area represenfd in (B) showing brightly refracfile silica particle in the center of the granuloma.

Variably sized amalgam particles may be introduced through abraded or lacerated mucosa during placement, removal, or recontouring of restorations,75 as well as through intact oral mucosa with the use of high-speed dental handpieces. 76,77If imbedded particles are individually large enough or collectively dense enough, they may be visible on radiographic examination.78 As the composition of amalgam changes over time, histology changes with it. Initially, the reaction is neutrophilic and lymphocytic with a rim of fibrin surrounding the process. 74 Smaller particles are phagocytized by macrophages, giant cells, endothelial cells, and fibroblasts.79 After four weeks, the reaction subsides and only a thin fibrous capsule surrounds amalgam. EDXA has provided both a means of study of the changes of amalgam composition over time and a definitive method to identify the metallic elements in tissue. With EDXA plumbism, bismuthiosis, argyria, or mercurialism can be excluded as causes of this type of hyperpigrnentaton.74

Occupationally Acquired Foreign Bodies Various materials may be lodged in skin in work-related circumstances. Of most dermatologic interest are argyria and berylliosis (Table 5). Although in years past argyria was associated with silver-containing oral and injectable medications,*“ currently it is observed in individuals who work in silver refineries, handle silver electroplating solutions, or are involved in photographic processing.s1 It has been estimated that as little as 4 - 5 grams of silver can produce the characteristic slate-grey hyperpigmentation.82 Histopathologically, the most significant abnormality is the accumulation of silver-containing granules in relation to the basement membrane of eccrine gland

secretory coils. Identification of this metallic element is readily accomplished with EDXA. Berylliosis is a disease that may result from exposure to metallic beryllium or its salt. Inhalation may result in acute or chronic pulmonary disease. Contact with soluble salts may result in acute contact dermatitis, whereas implantation of beryllium metal alloy or salts may cause inflammatory nodules with or without ulceration. Although many workers are exposed, few develop the disease.83 Occupations potentially at risk include beryllium, alloy, and scrap metal workers, manufacturers of ceramics (crucibles, jet engine blades, rocket covers, brake pads), manufacturers of transistors, heat sinks, and X-ray laboratory workers, and atomic energy windows, workers (rocket fuels, heat shields).83 The chronic form of beryllium disease may have a latent period of up to 20 years, 84 an aspect similar to granulomas caused by silica. The hislologic hallmark of berylliosis is the formation of epithelioid granulomas, without central necrosis in the systemic forms5 and with zones of necrosis in cutaneous nodules (Figure 8). *6 Beryllium is not detectable with EDXA. It can, however, be found in tissue using EELS or LAMMA. Measurable levels of beryllium may be found in lungs and lymph nodes of exposed persons who do not have clinical disease.87 Thus, documentation of a history of exposure, consistent clinical, radiologic, and histologic evidence, and hypersensitivity are also necessary in order to diagnose berylliosis.88

Self-Inflicted Foreign Bodies Patterns of substance abuse and attention-seeking selfabuse may manifest themselves as characteristic or bizarre cutaneous changes (Table 6). In the case of percuta-

Synthetic: acrylic, nylon’22 fingers, soles

lower leg, sites of trauma

umbilicated redpurple nodule & edema

wheat stubble’*l

small firm painless nodules

mostly extremities

purplish-red nodule(s)

spines”6-“8

splinters/ thornslWZO

sites of trauma

Distribution

primarily extremities

variably painful red papules

Clinical

clustered flesh dome-shaped papules

Plant: cactus

spines’15

sea urchin

Fibers

Change

Table 4. Traumatic Foreign Bodies

NR

NR

only)

+ (early

NR

NR

X-ray Studies

vacuoles & slits with fibrillar inclusions

epithelioid granulomas

rectangular material with cell walls

20 - 30 pm yellow barbs

non-caseating granulomas

Change

dermis & subcutis, epithelioid granulomas with giant cells

dermis, surrounding foreign body reaction dermis, subcutis; abscessformation, granulation tissue, foreign body reaction dermis

variable levels of dermis

Location

Light Microscopy

-

Polariscopy

NR

NR

NR

NR

NR

Darkfield

NR

NR

NR

NR

NR

Electron Microscopy

comparison of histochemishy of lesions with suspect fibers

PAS + rectangular cell walls

PAS + rectangular cell walls

PAS + spines

removal of spines, if present, history

Diagnostic Study

site of blast impact or abrasion mandibular gingivae, oral mucosa, surgical site

black-blue, grey-

site of previous laceration/ abrasion, in scar

inoculation site, soft tissues & distant locations

punctate greyblack discoloraiton

erythematous nodules, papules, h/or hyperpigmentation

erythematous subcutaneous masses or ulcerated nodules

may be +

NR

may be +

+ (local & distant sites)

extra & intracellular pigment granules black to goldenbrown granules, irregular clumps

noncasealing granulomas

dark grey to black opaque variably sized globules

(+) = positive; (-) = negative; ED = electron dense; PAS = periodic acid Schif’s; EDXA = electron dispersive X-q

Tattoo: Blast or Abrasion’23

Silica: glass, sand, land mine explosions”,68-72

Particulates

Metallies

-

NR

-I-

NR

+

NR

NR

+ (silvery)

extremely ED material in giant cells, fibroblasts, macrophages, may be membranebound

NR

SEM with BEI for localization of particles reported

spherical to eggshaped globules; adjacent necrosis

EDNA: silver, mercury, tin, copper &/or gold detected

none reported; clinical correlation

spectroscopy, EDXA: elemental silicon peak

gold lysis test; EDXA

analysis;SEM with BEI= scanning electron microscopy with bockscattered electron imaging.

basal lamina, in vessel walls, along endomysium &/or perineurium, may be surrounded by fibrosis

various levels of dermis

variable levels of dermis

dermal or subcutaneous; surrounding collagen necrosis & granulomatous inflammation

inflammatory papules, shallow pits, sinuses

cutaneous sclerosis; variable lung involvement

+/ulceration; may have lung involvement & adenopathy

nodular scars

slate-grey hyperpigmentation

Change

Distribution

= not

hairshafts in dermis

sclerosis & homogenization

epithelioid granulomas +/- central necrosis

small brownblack granules

Change

dermis with granulomatous infiltrate

deep dermis; (histologically morphea)

dermis; may have fibrosis peripheral to granulomas

basal lamina of epidermis, hair follicles, small vessels & free in dermis

Location

+

+ (exposed skin)

NR

NR

Polariscopy

Light Microscopy

-

NR

NR

+

Darkfield

NR

NR

NR

ecaine gland basal laminae & elastic fibers

epidermal &

30-100 run ED round to oval granules along

Electron Microscopy

reported; ED = electron dense; EDNA= electron dispersive X-ray analysts; LAMMS= Laser microprobe mass spectrometry.

subungual, interdigital, onycholysis

acral, extremity (ascending) or generalized

+/pulmonary changes

exposed skin

particularly in sun-exposed sites; proximal nails & cornea

Clinical

(+) = positive; (-) = negative; (+/-) = with or without; NR

hairdressers

miners, exposure to silica dust

miners, gold

metal, ceramic, electronics workers, atomic energy industry, beryllium extraction

silver refineries, photographic processing handling silver electroplating solutions

Trichonranuloma

Sfica’2”,‘25

Silicosis

Berylliume3-**

Berylliosis

Arnvria

Exposure

Table 5. Occuvational Foreian Bodies

clinical, H&E, polaroscopy

X-ray spectrophotometry; EDXA

EELS; LAMMS

EDNA: silver peak

Diagnostic Study

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ANALYSIS OF CUTANEOUS

JAWORSKY FOREIGN BODIES

173

Figure 8. Cutaneous berylliosis. A) Low-power view showing multiple dermal granulomas, some in a linear array. B) Highpower view of epithelioid granulomas without necrosis. C)

High-power view of epithelioid granulomas with prominent central necrosis characteristic of cutaneous nodules of beryllium disease.

neous substance abuse, powders or tablets are often dissolved in water prior to injection. Repetitive use of veins leads to occlusive sclerosis or “bum out,” after which subcutaneous injections (“skin popping”) may follow. The stigmata of intravenous drug abuse stem from use of unclean equipment used for repeated injections of unsterile, irritating solutions containing insoluble crystals. *9 Sequellae of injected drug abuse are thus septic (local abscesses, endocarditis), aseptic (hyperpigrnentation, soot tattoos, fibrosis, leukocytoclastic vasculitis), and granulomatous. Granulomatous reactions occur in response to tablet or powder fillers such as talc and cellulose. These polarizable materials can be found in granulomatous lesions in the dermis and subcutis, in larger caliber vessel walls and draining lymphatics, and in pulmonary parenchyma. 89,90The presence of these materials in pulmonary arterioles has led to pulmonary hypertension, car pulmonale, and death.90 Multiple local injections of pentazocine cause a characteristic woody induration of skin, soft tissues, and underlying muscle with ulceration. These changes appear related to ischemia mediated by a direct vasoconstictive and vasoocclusive effects of pentazocine.91 When the tablet form of pentazocine or meperidine is used for injections, talc is frequently detectable in affected tissues.92 Thus, characteristic cutaneous findings or observation of polarizable tablet fillers in tissues are diagnostic clues of substance abuse. Factitial dermatitis may have a bizarre clinical appearance, lack conformity to known diseases, may be predicted by patients, and is often limited to accessible sites.

Self-injection of various substances, including milk, feces, and mercury, has resulted in the clinical manifestations of factitial panniculitis. 93-95 In the latter instance the presence of mercury was documented with X-rays and serum mercury levels in a 13-year-old boy who injected mercury with his mother’s insulin syringes. Such cases exemplify attention-seeking maneuvers, which require psychiatric care in addition to therapy of the insult. Occasionally, where clinical findings are misinterpreted as factitial or self-inflicted, histologic examination and EDXA studies may help in arriving at the correct diagnosis. For example, suspected factitial panniculitis was shown by xeromammography to be migratory silicone granulomas from a ruptured breast prosthesis.46 Thus, in situations where substance abuse or attentionseeking behavior are suspected, finding foreign materials in the skin may have diagnostic value.

Summary Foreign materials from exogenous sources pose a constant challenge to the diagnostic skills of practicing dermatologists. Depending upon circumstances, radiologic, histologic, and ultrastructural techniques can be of assistance in ascertaining the presence and nature of the substance in question. With technologic advancements, identification of small-sized particles is no longer limited to morphologic study alone. Ultrastructural analytic techniques now permit identification of minute particles or quantities of material in tissues with relative ease. No doubt, further application of currently available and

extravasation of adulterant; arterial

injection sites; +/in vessel walls & pulmonary parenchyma

variably-sized ovoid cavities between histiocytes & macrophages; may contain oily droplets or film necrosis, abscesses, late fibrosis

presence of silicone

irritants, bacterial contamination

local or distant to implant sites

sites of injection

subcutaneous plaques & nodules

inflammatory nodules

silicone granulomas47.48

organic substances (milk, feces, other)93,94

W = positive;C-J = negative; NR = not reported; EDXA = electron dispersive X-ray analysis.

dark-grey to black, opaque globules

deposits of metallic mercury

injection sites; distant migration possible

tender, nonflu&ant masses

mercury injections64.95

dermis, subcutis

dermis, subcutis

dermis, subcutis

subcutaneous fat, may have calcification

acute panniculitis, necrosis, surrounding histiocytic response & fibrosis

probably presence of tablet fillers

buttocks, thighs, accessible sites injection sites

painful subcutaneous nodules

meperidine injectionP

Other /Factitial

dermis, subcutis, may extend to muscle

fibrosis, vascular thrombosis, occasional endarteritis

probable vasoocclusive & vasoconstrictive effects of drug

subcutis, in vessel walls, pulmonary

dermis, variable depths

Location

injection sites, often thighs & other accessible areas

variably-sized black intra- & extracellular pigment granules granulomatous inflammation

Change

Light Microscopy

woody induration +/- ulceration

embolization

tiCTO-

carbon residue on needle after flaming

Cause

injection sites

Distribution

Clinical

pentazocine injectionsgo92.128.129

Abuse

erythematous nodules

granulomatous lesionss9,‘0’

Narcotic/Analgesic

focal brown-black discoloration

soot tattooss9

Drug Abuse

Change

Foreign Bodies

Intravenous/Subcutaneous

Table 6. Self-Inflicted

NR

(if + adulterants present)

_

NR

+

(lactate, inj.)

+ (HCL, tablets) -

+

NR

Polariscopy

NR

NR

+ (silvery)

NR

NR

NR

NR

Darkfield

observation of behavior

mercury globules in pus, positive Xrays; identifiable with EDXA Xeroradiographs helpful, EDXA for definitive identification

polaroscopy for talc +/- EDXA; cellulose by X-ray diffraction & infrared absorption polaroscopy for crystalline material

talc by EDXA

clinical & H&E appearance

Method of Identification

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ANALYSIS OF CUTANEOUS

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175

newly evolving analytic systems will expand our limits of detection and enhance our scientific knowledge.

18. Forslind 8. Clinical applications of scanning electron microscopy and X-ray microanalysis in dermatology. Scanning Electron Microsc 1984;(Pt1):183-206.

References

19. Forslind B, Grudin TG, Lindberg M, et al. Recent advances in X-ray microanalysis in dermatology. Scanning Electron Microsc 1985;(Pt2):687-95.

1. Lammers RL. Soft tissue foreign bodies. Ann Emerg Med 1988;17:1336-47.

2. Fodor J, Malott JC. The radiographic detection of foreign bodies. Radio1 Tech 1983;54:361-69.

3. Starer F. The soft tissues. In Sutton D (ed). A Textbook of Radiology and Imaging, Fourth Ed. London, Churchill Livingstone, 1987, pp 1373-95.

4. Pick RY. The roentgenographic

appearance of lead paint as a foreign body. Clin Orthop 1981;155:305-06.

5. Bowers DG, Lynch JB. Xeroradiography

for non-metallic foreign bodies. Plast Reconstr Surg 1977;60:470-71.

20. Pickett JP, Ingram P, Shelbume JD. Identification of inorganic particulates in a single section using both light rnicroscopy and x-ray microprobe analysis. J Histotechnology 1980;3:155-58. 21. Forslind B. Clinical applications of scanning electron microscopy and energy dispersive X-ray analysis in dermatology-An update. Scanning Microsc 1988; 2:959 - 76.

6. Woesner ME, Sanders I. Xeroradiography:

22. Malmqvist KG, Carlsson LE, Forslind B, et al. Proton and electron microprobe analysis of human skin. Nucl Instr Meth Phys Res 1984;B3:61117.

7. Pond GD, Lindsey D. Localization of cactus, glass and

23. Burge KM, Winkelmann RK. Mercury pigmentation: An electron microscopic study. Arch Dermatol 1970;102:5161.

A significant modality in the detection of non-metallic foreign bodies in soft tissues. Am J Roentgen01 1972;115:636-40.

other foreign 34:700-02.

bodies

in soft tissues. Ariz Med 1977;

8. Curry TS, Dowdey JE, Murry RC, Jr. Christensen’s Introduction to the Physics of Diagnostic Radiology, Third Ed. Philadelphia, Lea & Febiger, 1984;319.

9. Tanita Y, Kato T, Hanada K, Tagami H. Blue macules of localized argyria caused by implanted acupuncture needles: Electron microscopy and roentgenographic microanalysis of deposited metal. Arch Dermatol 1985; 121:1550-52.

24. Engstrom A. X-ray microscope. In McGraw-Hill Encyclopedia of Science and Technology, Vol. 19. New York, McGraw-Hill Book Co., pp 564 - 66. 25. Pelachyk JM, Bergfeld WF, McMahon JT. Chrysiasis following gold therapy for rheumatoid arthritis: Ultrastructural analysis with x-ray energy spectroscopy. J Cutan Path01 1984;11:491-94. 26. Koch AG. Zur kenntnis der chrysiasis. Arch F Dermat Syph 1938;178:323.

of

27. Hashimoto A, Maeda Y, Ito H, et al. Cornea1 chrysiasis: A clinical study in rheumatoid arthritis patients receiving gold therapy. Arthritis Rheum 1972;15:309 - 12.

11. Stoughton R, Wells G. A histochemical study on polysaccarides in normal and diseased skin. J Invest Dermatol 1950;51:37-51.

28. Ghadilly FN, DeCoteau WE, Huang S, Thomas I. Ultrastructure of the skin of patients treated with sodium aurothiomalate. J Path01 1978;124:77-83.

12. Bloom W, Fawcett DW. A Textbook of Histology, Tenth Edition. Philadelphia, WB Saunders, 1975, pp 21-30.

29. Beckett VA, Doyle JA, Hadley GA, Spear KL. Chrysiasis resulting from gold therapy in rheumatoid arthritis: Identification of gold by X-ray microanalysis. Mayo Clin Proc 1982;57:773-77.

10. Imray TJ, Hiramatsu Y. Radiographic manifestations Japanese acupuncture. Radiology 1975;115:625-26.

13. Copenhaver WM, Kelley DE, Wood RL. Bailey’s Textbook of Histology, 17th Ed. Baltimore, Williams and Wilkins Co., 1987, pp 5-7. 14. Andres TL, Vallyathan V, Madison JF. Electron-probe microanalysis: Aid in the study of skin granulomas. Arch Dermatol 1980;116:1272-74.

30. Leonard PA, Moatamed F, Ward JR, et al. Chrysiasis: The role of sun exposure in dermal hyperpigmentation secondary to gold therapy. J Rheumatol 1986;13:58-64.

15. Hall TA, Rockert HOE, Saunders RLdeCH. X-Ray Microscopy in Clinical and Experimental Medicine. Springfield, Ill., Charles C. Thomas, 1972, pp 3-10.

31. Slater DN, Underwood JCE, Durrant TE, et al. Aluminum hydroxide granulomas: light and electron microscopic studies and X-ray microanalysis. Br J Dermatol 1982; 107:103-08.

16. Baker D, Kupke KG, Ingram P, et al. Microprobe analysis in human pathology. Scan Electron Microsc 1985;(Pt 2):659- 80.

32. Jordaan HF, Sandler M. Zinc-induced granuloma-A unique complication of insulin therapy. Clin Exp Dermato1 1989;14:227-29.

17. Johnson DE. Analytical electron microscopy in the study of biological systems. In Somlyo AP (ed). Recent Advances in Electron and Light Optical Imaging in Biology and Medicine. New York, The New York Academy of Sciences, 1986, pp 241-44.

33. D’Amico DJ, Kenyon KR, Ruskin JN. Amiodarone keratopathy. Arch Ophthalmol 1981;99:257-61. 34. Trimble JW, Mendelson DS, Fetter BF, et al. Cutaneous pigmentation secondary to amiodarone therapy. Arch Dermatol 1983;119:914-18.

176

JAWORSKY

Clinics in Dermatology 2991;9:157- 178

35. Zachary CB, Slater DN, Holt DW, et al. The pathogenesis of amiodarone-induced pigmentation and photosensitivity. Br J Dermatol 1984;110:451-56. 36. Hashimoto K, Wiener W, Albert J, Nelson RG. An electron microscopic study of chlorpromazine pigmentation. J Invest Dermatol 1966;47:296-306.

54. Findlay GH. Ochronosis following skin bleaching with hydroquinone. J Am Acad Dermatol 1982;6:1092-93. 55. Cullison D, Abele DC, O’Quinn JL. Localized exogenous ochronosis. J Am Acad Dermatol 1983;8:882-89. 56. Howard KL, Furner BF. Exogenous ochronosis in a Mexican-American woman. Cutis 1990;45: 180 - 82.

37. Benning TL, McCormack KM, Ingram P, et al. Microprobe analysis of chlorpromazine pigmentation. Arch Dermatol 1988;124:1541-44.

57. Hoshaw RA, Zimmerman KG, Menter A. Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks. Arch Dermatol 1985;121:105-08.

38. Sauer CC. Muddy skin from minocycline. 1979;29:3.

58. Hull PR, Procter PR. The melanocyte: An essential link in hydroquinone-induced ochronosis. J Am Acad Dermatol 1990;22:529-31.

Schoch Letter

39. Simons JJ, Morales A. Minocycline andgeneralizedcutaneous pigmentation. J Am Acad Dermatol 1980;3:244-47. 40. McGrae JD, Zelickson AE. Skin pigmentation secondary to minocycline therapy. Arch Dermatol 1980;116:1262-65. 41. Sato S, Murphy GF, Bernhard JD, et al. Ultrastructural and X-ray microanalytical observations of minocycline-related hyperpigmentation of the skin. J Invest Dermatol 1981;77:264-71.

59. Iwatsu T, Miyaji M. Phaeomycotic cyst: A case with a lesion containing a wooden splinter. Arch Dermatol 1984;120:1209-11. 60. Connor DH, Gibson DW. Association of splinters with chromomycosis and phaeomycotic cyst (letter). Arch Dermatol 1985;121:168.

as a

61. Rachman R. Soft-tissue injury by mercury from a broken thermometer. A case report and review of the literature. Am J Clin Path01 1974;61:296-300.

43. Fenske NA, Millns JL, Greer KE. Minocycline-induced pigmentation at sites of cutaneous inflammation. JAMA 1980;244:1103-06.

62. Arcadia F, Thivolet J, Perrot H. Acrodynia following the accidental subcutaneous infiltration of mercury. Bull Sot Br Dermatol 1968;75:609 - 10.

44. Okada N, Moriya K, Nishida K, et al. Skin pigmentation associated with minocycline therapy. Br J Dermatol 1989;121:247-54.

63. Popper L. Death following injury by a thermometer (Tod nach thermometerverletzung). Wien Med Wochenschr 1966;116:779-80.

45. Oertel VC, Johnson FB. Sclerosing lipogranuloma male genitalia. Arch Path01 1977;101:321-26.

64. Lupton GP, Kao GF, Johnson FB, et al. Cutaneous mercury granuloma. A clinicopathologic study and review of the literature. J Am Acad Dermatol 1985;12:296-303.

42. Basler RSW, Kohnen PW. Localized hemosiderosis sequela of acne. Arch Dermatol 1987;114:1695-97.

of the

46. Delage C, Shane JJ, Johnson FB. Mammary silicone granuloma: Migration of silicone fluid to abdominal wall and inguinal region. Arch Dermatol 1973;108:104-07.

65. Hill DM. Self-administration of mercury by subcutaneous injection. Br Med J 1967;1:342-43.

47. Travis WD, Balogh K, Abraham JL. Silicone granulomas: Report of three cases and review of the literature. Hum Path01 1985;16:19-27.

66. Conrad ME, Sanford JP, Preston JA. Metallic mercury embolization: Clinical and experimental. Arch Intern Med 1957;100:59-65.

48. Mason J, Apisamthanarax I’. Migratory silicone granuloma. Arch Dermatol 1981;117:366-67.

67. Buxton JT, Hewitt JC, Gadsden RH, Bradham GB. Metallic mercury embolism. JAMA 1965;193:573-75.

49. Hausner RJ, Schoen FJ, Mendez-Fernandez MA, et al. Migration of silicone gel to axillary lymph nodes after prosthetic mammoplasty. Arch Path01 Lab Med 1981; 105:371-72.

68. Shelley WB, Hurley HJ. The pathogenesis of silica granulomas in man: A nonallergic colloidal phenomenon. J Invest Dermatol 1960;34:107-22.

50. Kircher T. Silicone lymphadenopathy. A complication of silicone elastomer finger joint prostheses. Hum Path01 1980;11:240-44. 51. Leong ASY, Disney AI’S, Gove DW. Spallation and migration of silicone from blood-pump tubing in patients on hemodialysis. N Engl J Med 1982;306:135-40. 52. Orenstein JM, Sato N, Aaron B, et al. Microemboli observed in deaths following cardiopulmonary bypass surgery: Silicone antifoam agents and polyvinyl chloride tubing as sources of emboli. Hum Path01 1982;13:1082-90. 53. Ellenbogen R, Ellenbogen R, Rubin L. Injectable fluid silicone therapy: Human morbidity and mortality. JAMA 1975;234:308-09.

69. Eskeland G, Langmark F, Husby G. Silicon granuloma of the skin and subcutaneous tissue. Acta Path01 Microbial Stand [A] Suppl 1974;248:69 - 71. 70. Rank BK, Hicks JD, Lovie M. Pseudotuberculoma losum silicotium. Br J Plast Surg 1972;25:42-48.

granu-

71. Crossland PM. Silicon granuloma of the skin. Arch Dermatol Syphilol 1955;71:457-61. 72. Mesquita-Guimaraes J, Azevedo F, Aguiar S. Silica granulomas secondary to explosion of a land mine. Cutis 1987;40:41-43. 73. Chan SD. Amalgam tattoos (localized argyria): A review of the literature. Georgetown Dent J 1978;42:31-35. 74. Hatch CL, Terezhalmy GT, Krolls SO. Amalgam tattoos of the oral soft tissue. Ear Nose Throat J 1984;63:416-22.

Clinics in Dermatology 1991;9:157-178

ANALYSIS OF CUTANEOUS

75. Buchner A, Hansen LS. Amalgam pigmentation (amalgam tattoo) of the oral mucosa. Oral Surg 1980;49:139-47. 76. Weathers DR, Fine RM. Amalgam tattoo of the oral mucosa. Arch Dermatol 1974;110:727-28. 77. Eley BM. The fate of amalgam implanted in soft tissuesAn experimental study. J Dent Res 1979;58:1146-52. 78. Hartman LC, Natiella JR, Meenaghan MA. The use of elemental microanalysis in verification of the composition of presumptive amalgam tattoo. J Oral Maxillofac Surg 1986;44:628-33.

JAWORSKY FOREIGN BODIES

177

96. Bhawan J. Steroid-induced “granulomas” in hypertrophic scar. Acta Venerol (Stockh) 1983;63:560-63. 97. Morgan AM, Johnson FB, Lupton GP. Cutaneous and subcutaneous polyvinylpyrrolidine (PVP) storage disease. J Cutan Path01 1989;16:318A. 98. Thivolet J, Leung TK, Duveme J, et al. Ultrastructural morphology and histochemistry (acid phosphatase) of the cutaneous infiltration by polyvinylpyrrolidine. Br J Dermatol 1970;83:661-69. 99. Tuffanelli D, Abraham RK, Dubois EL Pigmentation from antimalarial therapy. Arch Dermatol 1963;88:113-20.

79. Harrison JD, Rowly PSA, Peters PD. Amalgam tattoos: Light and electron microscopy and electron-probe microanalysis. J Path01 1977;121:83-92.

100. Venencie PY, Cortez A, Orieux G, et al. Clofazimine enteropathy. J Am Acad Dermatol 1986;15:290-91.

80. Shelley WB, Shelly ED, Burmeister V. Argyria: The intradermal “photograph’, a manifestation of passive photosensitivity. J Am Acad Dermatol 1987;16:211-17.

101. Hays GB, Lyle CB, Wheeler CE. Slate-gray color in patients receiving chlorpromazine. Arch Dermatol 1964; 90:471- 76.

81. Bleehen SS, Gould DJ, Harrington Cl, et al. Occupational argyria: Light and electron microscopic studies and X-ray microanalysis. Br J Dermatol 1981;104:19-26.

102. Hashimoto K, Joselew SA, Tye MJ. Slate-gray hyperpigmentation by long term administration of imipramine. J Cutan Path01 1989;16:306A.

82. Siemund J, Stolp A. Argyrose. 1968;43 (Suppl):71- 74.

103. Dupre A. Touron P. Daste J, et al. Titanium pigmentation: An electron probe microanalysis. Arch Dermatol 1985;121:656-58.

83. Jones Williams W. Beryllium 1988;64:511-16.

Z Haut Geschlechtskr

disease. Postgrad

Med J

84. Jones Williams W. UK beryllium case registry 1984- 1985. J Path01 1985;146:284A. 85. Stoeckle JD, Hardy HL, Weber AL. Chronic beryllium disease. Am J Med 1967;46:545-57. 86. Neave HJ, Frank SB, Tolmach J. Cutaneous granulomas following laceration by fluorescent light bulbs. Arch Dermatol Syph 1950;61:401-06. 87. Daniele RI’, Elias JA, Epstein FE, Rossman MD. Bronchoalveolar lavage: Role in the pathogenesis, diagnosis and management of interstitial lung disease. Ann Intern Med 1985;102:93-108. 88. Jones Williams W. Beryllium disease-pathology diagnosis. J Sot Occup Med 1977;27:93-96. 89. Hirsch CS. Dermatopathology Path01 1972;3:37-53.

and

of narcotic addiction. Hum

90. Houck RJ, Bailey CL, Daroca PJ, et al. Pentazocine abuse. Report of a case with pulmonary arterial cellulose granulomas and pulmonary hypertension. Chest 1980;77:22730.

104. Terzakis JA, Shustak SR, Stock EG. Talc granuloma identified by X-ray microanalysis. JAMA 1978;239:237172. 105. Leonard DD. Starch 1973;107:101103.

granulomas.

Arch

Dermatol

106. Apfelberg DB, Manchester GH. Decorative and traumatic tattoo biophysics and removal. Clin Plast Surg 1987;14:243-51. 107. Abel EA, Silberberg I, Queen D. Studies of chronic inflammation in a red tattoo by electron microscopy and histochemistry. Acta Derm Venereol (Stockh) 1972;52:45361. 108. Alagaratnam TT, Ong GB. Paraffinomas J R Co11 Surg Edinb 1983;28:260-63.

of the breast.

109. Nakamura M, Saekrai T, Yoshida K, et al. Sclerosing lipogranuloma of the penis: Chemical analysis of lipid from lesional tissue. J Urol 1985;133:1046-48. 110. Stegman SJ, Chu S, Armstrong RC. Adverse reactions to bovine collagen implant: Clinical and histologic features. J Dermatol Surg Oncol 1988:14(Suppl 1):39-48.

9 1. Parks DL, Perry HO, Muller SA. Cutaneous complications of pentazocine injections. Arch Dermatol 1971;104:23135.

111. Stegman SJ, Chu B, Bensch K, Armstrong R. A light and electron microscopic evaluation of Zyderm collagen and Zyplast implants in aging human facial skin: A pilot study. Arch Dermatol 1987;123:1644-49.

92. Forstrom L, Winkelmann RK. Factitial panniculitis. Arch Dermatol 1974;110:747-50.

112. Lamar LM, Bliss 80. Localized pigmentation of the skin due to topical mercury. Arch Dermatol 1966;93:450-53.

93. Ackerman AB, Mosher DT, Schwamm HA. Factitial Weber-Christian syndrome. JAMA 1966;198:731-36.

113. Shelley WB, Hurley HJ. The allergic origin of zirconium deodorant granulomas. Br J Dermatol 1958;70:75-101.

94. Sullivan M. Trosow A. Multiple subcutaneous abscesses produced by the hypodermic injection of feces. South Med J 1949;42:402-04.

114. Hirsh BC, Johnson WC. Pathology of granulomatous diseases: Epithelioid granulomas part II. Int J Dermatol 1984;23:30613.

95. Krohn IT, Solof A, Mobini J, Wagner DK. Subcutaneous injection of metallic mercury. JAMA 1980;243:548-49.

115. Kinmont PDC. Sea-urchin sarcoidal granuloma. Br J Dermatol 1965;77:335-43.

178 JAWORSKY

116. Winer LH, Zeilenga RH. Cactus granulomas of the skin. Arch Dermatol 1955;72:566-69. 117. Snyder RA, Schwartz RA. Cactus bristle implantation: Report of an unusual case initially seen with rows of yellow hairs. Arch Dermatol 1983;119:152-54. 118. Lindsey D, Lindsey WE. Cactus spine injuries, Am J Emerg Med 1988;6:362-69. 119. Mehregan AH, Faghri B. Implantation dermatoses. Acta Dermato Venereol (Stockh) 1974;54:61-64.

Clinics in Dermatology 1991;9:157-278 123. Hanke CW, Conner AC, Probst EL, Fondak AA. Blast tattoos resulting from black powder firearms. J Am Acad Dermatol 1987;17:819-25. 124. Rustin MHA, Bull HA, Ziegler V, et al. Serological abnormalities and clinical features of silica associated systemic sclerosis. J Invest Dermatol 1988;91:403A. 125. Haustein U-F, Ziegler V, Herrmann K, et al. Silica-induced scleroderma. J Am Acad Dermatol 1990;22:444-48. 126. Stubbart FJ. Onycholysis of the fingernails of beauticians due to imbedded hair. Arch Dermatol 1956;74:430.

120. Hirsh BC, Johnson WC. Pathology of granulomatous diseases: Foreign body granulomas. Int J Dermatol 1984; 23:531-38.

127. Hogan DJ. Subungual trichogranuloma Cutis 1988;42:105-06.

121. Cortez Pimentel J. The “wheat-stubble sarcoid granuloma”: A new epithelioid granuloma of the skin. Br J Dermatol 1972;87:444-49.

128. Padilla AS, Becker LE, Hoffman H. Cutaneous andvenous complications of pentazocine abuse. Arch Dermatol 1979;115:975-77.

122. Cortez Pimentel. Sarcoid granulomas of the skin produced by acrylic and nylon fibres. Br J Dermatol 1977;96:67377.

129. Posner DI, Guill MA. Cutaneous foreign body granulomas associated with intravenous drug abuse. J Am Acad Dermatol 1985:13:869-72.

in a hairdresser.