Are You Confident of the Diagnosis?
What you should be alert for in the history
History of accidental, intentional, or iatrogenic introduction of an exogenous foreign material into the body at the site of the reaction is a very helpful clue to the diagnosis; although, because of the delayed onset of this condition, some patients may not recall the inciting event. In addition, some endogenous materials, such as keratin and urate crystals, can induce a foreign body granuloma, and in these situations, there will not be a history of inoculation.
Usually, an acute inflammatory reaction occurs shortly after introduction of the foreign body and may resolve. After a varying amount of time (days, weeks, months, or years) a chronic inflammatory reaction occurs that persists.
Characteristic findings on physical examination
Clinical findings can be variable, depending on the individual host response. The lesions tend to be asymptomatic, or can take the form of tender pink, red, or red-brown firm papules, nodules, or plaques that may or may not ulcerate or drain.
Other presentations include sinus tracts and abscesses. An important clue is that these lesions occur in an arrangement localized to the area of inoculation (Figure 1); however, as is the case with silicone, the foreign material may migrate, leading to granulomas at sites distant from the area of implantation.
In those situations where an endogenous material is the cause of the granuloma, look for evidence of an underlying skin condition such as pseudofolliculitis barbae (PFB), acne keloidalis nuchae (AKN), an ingrown nail, the punctum of an epidermoid cyst, or a characteristic pilonidal sinus (cyst).
Expected results of diagnostic studies
Imaging studies, such as ultrasonography, radiography, computed tomography (CT), and magnetic resonance imaging (MRI), are not recommended, as they often cannot identify small cutaneous foreign bodies, even if they are radiopaque. Punch or excisional biopsy of a lesion sent for routine histology will determine the granulomatous nature of the reaction.
There are groups of epithelioid histiocytes with abundant cytoplasm. These epithelioid histiocytes coalesce and form the characteristic foreign body giant cells, which have numerous nuclei irregularly distributed in the cytoplasm (Figure 2).
Lymphocytes are also present in the inflammatory infiltrate. Plasma cells and eosinophils can be identified in some chronic foreign body granulomas as well. Some foreign body reactions (ie, those due to keratin, suture, tattoo ink, paraffin, bovine collagen, and hyaluronic acid, among others) have a distinctive pathology.
Polarized light microscopy is a useful adjunct to normal light microscopy of hematoxylin and hematoxylin and eosin (H&E) stained specimens (Figure 3). Some centers have access to more sophisticated procedures to help identify the exact nature of a foreign body. These procedures include electron spectroscopy for chemical analysis (ESCA), energy dispersive x-ray analysis (EDXA), electron energy loss spectroscopy (EELS), laser microprobe mass analysis, and infrared spectrophotometry (IRS) (see Table I).
|Foreign Body||Distinctive Clinical and Histologic Features||Other Detection Methods|
|Tattoo ink||Induration in only one color of tattoo (most commonly red, but can be any color)Pigment granules (most appear black) both within and outside macrophages||EDXA|
|Paraffin||Nodules, plaques, ulcers, or abscesses, most commonly on the penis or breast“Swiss cheese” cystic spaces of varying sizeStains with lipid stain (e.g. oil red O) on fresh tissue||IRSThin layer chromatography|
|Silicone||Can present at areas distant from implantation“Swiss cheese” cystic spaces of varying sizeDoes not stain with fat stain||ESCAEDXAScanning electron microscopyRadiopaque on x-ray|
|Silica||Nodules with or without hyperpigmentation within a scarCrystalline particles that are birefringent with polarized light||Bluish-white autofluorescence with fluorescence microscopyIRSEDXA|
|Talc||Involvement of scars, intertriginous areas, injection sites in IV drug users, umbilical stumpsBirefringent particles with polarized light||EDXA|
|Starch||Birefringent “Maltese cross” particles with polarized lightStain with PAS|
|Zirconium||Involvement of axillae (from antiperspirants)||EDXA|
|Beryllium||Localized cutaneous after trauma with broken fluorescent tubes (historical)Multiple cutaneous papules in patients with systemic berylliosis (occupational inhalation)||EELS|
|Aluminum||Nodules at vaccination or immunotherapy injection siteHistiocytes with abundant, PAS-positive, gray-purple cytoplasm||EDXA|
|Zinc||Sterile furuncles at the site of insulin injectionBirefringent particles with polarized light||EDXA|
|Bovine collagen (Zyderm/Zyplast)||Homogeneous, thick collagen bundles with minimal space in betweenNon-birefringent with polarized light (in contrast to human collagen)||Masson trichrome stains pale gray-violet in contrast to the blue or green staining of human collagenImmunohistochemical staining with anti-bovine collagen I antibody|
|Hyaluronic acid (Hylaform/Restylane/Juvéderm/Macrolane)||Amorphous basophilic material that stains with mucin stains (e.g. alcian blue pH 2.7 or colloidal iron)|
|Polymethylmethacrylate (PMMA) with bovine collagen (Artefill/Artecoll/Arteplast)||Uniform round nonbirefringent bodies in cystic spaces|
|Poly(hydroxyl)ethylmethacrylate with hyaluronic acid (DermaLive/DermaDeep)||Irregular polygonal, pink, nonbirefringent particles that resemble broken glass in cystic spaces|
|Poly-L-lactic acid (Sculptra/New-Fill)||Irregular fusiform, oval and spiky birefringent particles in cystic spaces that resemble suture material|
|Calcium hydroxylapatite (Radiance/Radiesse)||Blue-gray round or oval microspheres|
|Polyvinylpyrrolidone-silicone suspension (Bioplastique)||Irregular cystic spaces containing translucent jagged “popcorn” nonbirefringent particles|
|Wood splinters/cactus spines||Papule with a central black dotBirefringent material with polarized lightStain with PAS|
|Keratin||In setting of pseudofolliculitis barbae, acne keloidalis nuchae, ruptured epidermoid cysts, ingrown nails, and pilonidal sinusesVariably birefringent keratin flakes or hair shaftsStain with acid-fast stains||Immunohistochemical staining with anti-keratin antibodies|
|Arthropod parts||Birefringent material with polarized lightStain with PAS|
|Suture||Nodules within a surgical scar or an inflamed wound that can develop a fistulaBirefringent fibers with polarized light|
|Urate crystals||Nodules at joints or ear helicesAmorphous pink material in formalin-fixed tissue||Alcohol-fixed tissue preserves the birefringent crystals that stain with silver stains|
EELS – electron energy loss spectroscopy
ESCA – electron spectroscopy for chemical analysis
IRS – infrared spectrophotometry
EDXA – energy dispersive x-ray analysis
PAS – periodic acid-Schiff
PMMA – Polymethylmethacrylate
The differential diagnosis, both clinically and histologically, includes fungal and mycobacterial infections, leishmaniasis, and sarcoidosis. Special stains, such as periodic acid-Schiff (PAS), Grocott’s methenamine silver (GMS), acid-fast, and Giemsa, as well as tissue cultures should be performed if clinically indicated. The identification of foreign material within a sarcoidal granuloma does not exclude sarcoidosis, since granulomas in patients with sarcoidosis are sometimes attracted to previous areas of trauma. If systemic sarcoidosis is suspected, an appropriate workup is recommended.
Who is at Risk for Developing this Disease?
People of any age or ethnicity, and of either sex, can develop a foreign body granuloma if exposed to an inciting foreign material. Hence, patients that have had such exposures through hobbies (splinters, cactus spines, arthropod parts), accidents (silica), surgical procedures (talc, starch, suture), cosmetic procedures (bovine collagen, hyaluronic acid, paraffin, silicone, and others), tattooing, or intravenous drug abuse (talc used as filler for tablets), are at an overall increased risk.
In particular, patients that demonstrate hypersensitivity to bovine collagen are at an increased risk of developing foreign body granulomas at injection sites and so it is recommended that skin testing be performed by injecting 0.1mL of bovine collagen into the forearm of the patient and waiting for at least 30 days before injecting the desired site. Some authors suggest repeating this skin test 2-4 weeks after a negative test, as some patients will develop hypersensitivity after their first exposure. Even with a negative skin test, some patients have developed granulomas at the site of cosmetic injection.
Patients with certain dermatologic conditions, such as pseudofolliculitis barbae, acne keloidalis nuchae, ingrown nails, epidermoid cysts, and pilonidal sinus, are at increased risk of keratin granulomas. In addition, patients with sarcoidosis are more likely to develop sarcoidal granulomas at sites of previous trauma with identifiable foreign material.
What is the Cause of the Disease?
A foreign body granuloma is a manifestation of the skin’s immune system, which defends against “non-self” materials.
The development of foreign body granulomas is thought to be under the control of both the humoral and cell-mediated immune system pathways and most likely represents a type IV hypersensitivity reaction to a foreign antigen.
The initial response to most foreign materials is the recruitment of neutrophils to the site. The neutrophils are unable to adequately eradicate the foreign material and so monocytes and macrophages are attracted to the area to engulf (phagocytose) the foreign material. Activated macrophages produce a wide range of cytokines that attract more chronic inflammatory cells, including lymphocytes. Formation of multinucleated giant cells is a T helper cell 1 (Th1) response, mediated by the cytokines interleukin-2 (IL-2) and interferon-gamma. Essentially, the granulomatous response is an attempt by the body to “wall off” the foreign material.
Systemic Implications and Complications
Patients with sarcoidosis are more likely to develop sarcoidal granulomas at sites containing foreign material; for example, a patient presenting with granulomas in more than one color of a tattoo should be suspected of having sarcoidosis.
It has been proposed that sarcoidosis occurs when a genetically susceptible person is exposed to an environmental antigen. An exaggerated Th1 immune response ensues, which ultimately leads to granulomatous inflammation. It is also hypothesized that patients with sarcoidosis have an altered immune response to foreign material and, in fact, undetectable foreign material may be the trigger for the granulomatous inflammation in organs, including the skin, of patients with sarcoidosis. If systemic sarcoidosis is suspected in a patient presenting with a foreign body granuloma, an appropriate workup is recommended.
Treatment options are summarized in Table II.
|Foreign Body||Topical Medical Treatment||Intralesional Medical Treatment||Systemic Medical Treatment||Surgical Treatment||Physical Modalities||Other|
|Tattoo ink||Corticosteroids||Corticosteroids||Corticosteroids||Excision||Pulsed carbon dioxide laser (Q-switched laser is contraindicated for tattoos with granulomatous reactions)|
|Paraffin||Excision with tissue reconstruction|
|Silicone||Imiquimod||Corticosteroids||Minocycline or doxycycline 100mg once to twice daily with or without celecoxib 200mg twice dailyIsotretinoin 20mg daily for 6 months||Excision|
|Silica||Excision||Observation (few spontaneously resolve)|
|Talc||Excision||Observation (few spontaneously resolve)|
|Zirconium, beryllium, aluminum, zinc||Corticosteroids||Corticosteroids||Excision||Observation|
|Bovine collagen||Corticosteroids Tacrolimus 0.1% twice daily||Corticosteroids||Corticosteroids up to 60mg/day; Cyclosporine up to 5mg/kg/day||Observation (usually resolves as material degrades)|
|Hyaluronic acid (HA)||Corticosteroids||Corticosteroids 2.5-10mg/ mLHyaluronidase 150U/mL (0.5mL combined with 1.5mL of 1% lidocaine with epinephrine)–not into inflamed lesions||Corticosteroids up to 60mg/day Minocycline 250mg twice daily for one week
clarithromycin 500mg twice daily
|Extrusion of HA with a #11 blade||Observation (usually resolves as material degrades)|
|PMMA||Corticosteroids 2.5-10mg/mL in anesthetic solution5-fluorouracil (0.9mL of 5-FU 50mg/mL mixed with 0.1mL of triamcinolone 10mg/mL) given in 0.05mL aliquots every 2-4 weeks||Allopurinol 200-600mg daily||ExcisionAutologous fat transplantation|
|Poly(hydroxyl)ethylmethacrylate||Corticosteroids 2.5-10mg/mL5-fluorouracil (250mg/mL 5-FU mixed with triamcinolone 10mg/mL and 1mL of 1% lidocaine) injected with 27-G needle every 2-4 weeks||Allopurinol 200-600mg daily for average of one year||Excision|
|Poly-L-lactic acid||Corticosteroids||CorticosteroidsIbuprofen 1800-2400mg dailyAllopurinol 400mg dailyMinocycline 200mg dailyHydroxychloroquine 6mg/kg daily|
|Calcium hydroxylapatite||Corticosteroids 2.5-10mg/mL with massage||Excision||Avoid lip area for injections (increased risk of nodules)|
|Wood splinter/ cactus spine/ arthropod parts||BiopsyExcision|
|Keratin||For pseudofolliculitis barbae (PFB) and acne keloidalis nuchae (AKN), retinoids, glycolic acid, and/or clindamycin||Corticosteroids||Excision||For PFB, AKN, and pilonidal sinus, laser hair removal with long-pulsed lasers (alexandrite, 810nm diode or Nd:YAG)||For PFB and AKN, avoid shaving or, if clean-shaven look desired, shave everyday in the direction of hair growth and lift any ingrowing hairs prior to shaving|
|Suture||Corticosteroids||Manual extrusion of sutureExcision||Observation for spontaneous extrusion of suture|
|Urate crystals||Colchicine AllopurinolPEG-uricase||Excision||Reduction of purine-rich foods|
Optimal Therapeutic Approach for this Disease
For those foreign body granulomas that may spontaneously resolve (i.e., silica, talc, zirconium, beryllium, aluminum, zinc; and the non-permanent fillers, bovine collagen and hyaluronic acid), observation should be the first course of action. Obviously, since these granulomas may be in cosmetically sensitive areas and can be tender, the patient may desire some form of treatment rather than waiting the months it may take for the nodules to resolve.
The treatments with the least amount of risk, including topical and intralesional corticosteroids at appropriate strengths to avoid atrophy, would be first-line therapy. For a facial location, a class 3 or 4 topical steroid such as mometasone or triamcinolone 0.1% could be used for 3 to 4 weeks; the treatment could then be switched to a class 6 steroid such as desonide or alclometasone.
For a granulomatous reaction to hyaluronic acid, intralesional hyaluronidase or extrusion using a #11 blade could be considered before corticosteroids, although caution should be taken with injecting hyaluronidase into actively inflamed areas. Topical tacrolimus has also been used in patients with granulomas from bovine collagen, and this would be a reasonable first-line choice as well. If these modalities are unsuccessful, systemic treatments could be considered as second-line therapy. Choices include corticosteroids, cyclosporine, and minocycline. Finally, in recalcitrant lesions, excision can be performed; however, the cosmetic benefit of this should be considered.
For foreign body granulomas that do not spontaneously resolve (tattoo ink, paraffin, silicone, poly(methyl methacrylate) [PMMA], poly(hydroxyethyl methacrylate), poly-L-lactic acid, calcium hydroxylapatite, keratin, and urate crystals), observation is not an option if the patient desires resolution. First-line therapy for these depend on the specific foreign material involved (see Table II); but overall, topical and intralesional therapy would have the least risk, followed by systemic therapy, and finally surgical modalities, including carbon dioxide laser tattoo removal, keeping in mind whether the cosmetic result (carbon dioxide laser has an increased risk of scarring) would be better than the appearance of the nodules themselves.
The reports of the various medical therapies are all essentially anecdotal, making it difficult to say which would be most effective for any given patient. A discussion with the patient of the risks and potential benefits of each treatment modality in the context of the extent of their granulomatous disease is imperative.
For wood splinters, cactus spines, and suture material, the granulomas tend to be isolated and so can often be treated by biopsy or small excision. Suture material may even extrude on its own with little or no manual assistance; intralesional corticosteroids can also be tried for suture granulomas prior to more invasive surgical procedures.
Keratin granulomas can be caused by a variety of skin conditions, including ruptured epidermoid cysts, PFB, ingrown nails, pilonidal sinuses, and implantation of hair into the finger webspaces in barbers. The granulomas in PFB and AKN are best treated by the preventive techniques listed above. Ruptured epidermoid cysts can initially be treated with intralesional corticosteroids, but if they recur, excision is often necessary. Conservative treatment of ingrown nails includes placing gauze between the lateral nail plate and lateral nail fold, and also bracing the nail. Chronic ingrown nails will need surgical intervention for resolution. Laser hair removal can be attempted to treat pilonidal sinuses and hair granulomas in barbers, with excision as definitive treatment of recurrent or recalcitrant lesions.
Patients presenting with urate crystal granulomas (gouty tophi) need to have their underlying chronic tophaceous gout treated. The tophi themselves can be excised.
If a patient is being actively treated for a foreign body granuloma, frequent follow-up is recommended to monitor for response to the treatment. Intralesional injections should be given approximately every 4 weeks. Since many of the treatment recommendations for foreign body granulomas are anecdotal or based on small case series, the exact time frame to expect results, and switch therapy if a patient is unresponsive, is quite subjective. Close follow-up will allow the clinician to appreciate even small interval changes in the patient’s condition.
Clinical photographs taken at each appointment can also be helpful in determining if the patient is responding to treatment. It is important to caution a patient who has developed foreign body granulomas from an injectable filler agent against subsequent filler therapy of any kind, except for possibly autologous fat transplantation (see Table II). For patients with tattoo ink granulomas, avoidance of future tattooing is preferable; however, if patients insist on further tattooing, they must make sure that the tattoo ink does not contain any of the materials in the color that caused the granuloma (most tattoo colors contain a number of pigments, metal salts, and/or organic compounds combined to create the hue).
Unusual Clinical Scenarios to Consider in Patient Management
Vigilance must be maintained in patients presenting with foreign body granulomas to identify the occasional associated systemic disease such as sarcoidosis (see above), or the much more rare berylliosis, which can occur after occupational inhalation of beryllium.
Additionally, on occasion patients will inject themselves with a foreign body for secondary gain or as part of a psychiatric illness. In these cases, individuals should be referred to the appropriate caregivers for psychological counseling.
What is the Evidence?
Requena, L, Requena, C, Christensen, L, Zimmermann, US, Kutzner, H, Cerroni, L. “Adverse reactions to injectable soft tissue fillers”. J Am Acad Dermatol. vol. 64. 2011. pp. 1-34. (In this comprehensive review, the authors discuss the most commonly used fillers, the most common adverse reactions, as well as the characteristic histopathologic findings that allow the identification of the injected filler agent.)
Hirsch, BC, Johnson, WC. “Pathology of granulomatous diseases: foreign body granulomas”. Int J Dermatol. vol. 23. 1984. pp. 531-8. (In this review, the authors discuss the distinguishing clinical and histopathologic findings in various foreign body granulomas.)
Hirsch, BC, Johnson, WC. “Pathology of granulomatous diseases: epithelioid granulomas, part II”. Int J Dermatol. vol. 23. 1984. pp. 306-13. (In this review, the authors discuss the distinguishing clinical and histopathologic findings in various epithelioid granulomas, including zirconium and beryllium granuloma.)
Jaworsky, C. “Analysis of cutaneous foreign bodies”. Clin Dermatol. vol. 9. 1991. pp. 157-78. (In this review, the author discusses the various modalities available for identification of cutaneous foreign bodies.)
Bentkover, SH. “The biology of facial fillers”. Facial Plast Surg. vol. 25. 2009. pp. 73-85. (The author explains the biology of facial fillers, including the biology of phagocytosis and granulomatous inflammation.)
De Boule, K. “Management of complications after implantation of fillers”. J Cosmet Dermatol. vol. 3. 2004. pp. 2-15. (In this review, the author discusses treatment options for complications arising from injectable fillers.)
Marcoval, J, Mana, J, Moreno, A, Gallego, I, Fortuno, Y, Peyri, J. “Foreign bodies in granulomatous cutaneous lesions in patients with systemic sarcoidosis”. Arch Dermatol. vol. 137. 2001. pp. 427-30. (In this study of 425 patients with systemic sarcoidosis, 65 patients had cutaneous lesions that demonstrated granulomatous inflammation on biopsy. biopsy specimens showed granulomatous cutaneous involvement. In fourteen (22%) of the patients, foreign particles were observed under polarized light. This study confirms that polarizable material within a cutaneous granuloma does not exclude a diagnosis of systemic sarcoidosis and, in fact, polarizable foreign material is not uncommon in the cutaneous lesions of these patients.)
Kilmer, SL. “Laser treatment of tattoos”. Dermatol Clin. vol. 15. 1997. pp. 409-17. (The various lasers available for tattoo removal, as well as the recommended procedure protocol, are reviewed.)
Wiest, LG, Stolz, W, Schroeder, JA. “Electron microscopic documentation of late changes in permanent fillers and clinical management of granulomas in affected patients”. Dermatol Surg. vol. 35. 2009. pp. 1681-8. (Among ten patients that had delayed onset inflammatory nodules after injection with hydroxyethylmethacrylate and ethylmethacrylate with hyaluronic acid, all ten had a good response to a combination of oral allopurinol and intralesional 5-fluorouracil mixed with triamcinolone.)
Narins, RS, Jewell, M, Rubin, M, Cohen, J, Strobos, J. “Clinical conference: management of rare events following dermal fillers—focal necrosis and angry red bumps”. Dermatol Surg. vol. 32. 2006. pp. 426-34. (In this review, the authors discuss two rare side effects following hyaluronic acid dermal filler injection, and include an algorithmic approach to the patient with delayed onset angry red bumps after hyaluronic acid [HA] injection.)
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