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Figure 1.
Standard histologic analysis (hematoxylin-eosin). A, Focal vacuolization in basal and suprabasal keratinocytes (original magnification ×100). B, Diffuse vacuolization in basal layers associated with swelling and pallor of the upper epidermis (original magnification ×250). C, Subepidermal cleavage (asterisk) and cell vacuolization (original magnification ×100).

Standard histologic analysis (hematoxylin-eosin). A, Focal vacuolization in basal and suprabasal keratinocytes (original magnification ×100). B, Diffuse vacuolization in basal layers associated with swelling and pallor of the upper epidermis (original magnification ×250). C, Subepidermal cleavage (asterisk) and cell vacuolization (original magnification ×100).

Figure 2.
Electron microscopic analysis. Small (A) (arrows) or large (B) (asterisks) cytoplasmic and perinuclear vacuoles within keratinocytes (Ke); N indicates nucleus (original magnification ×2500). C, Widening of spaces (asterisks) between keratinocytes leading to rupture (black arrow) or stretching (white arrow) of membrane interdigitations without splitting of desmosomes (arrowheads) (original magnification ×8000). D, Cytoplasmic vacuoles surrounded by a membrane in a fibroblast of superficial dermis (De). Co indicates collagen (original magnification ×6200).

Electron microscopic analysis. Small (A) (arrows) or large (B) (asterisks) cytoplasmic and perinuclear vacuoles within keratinocytes (Ke); N indicates nucleus (original magnification ×2500). C, Widening of spaces (asterisks) between keratinocytes leading to rupture (black arrow) or stretching (white arrow) of membrane interdigitations without splitting of desmosomes (arrowheads) (original magnification ×8000). D, Cytoplasmic vacuoles surrounded by a membrane in a fibroblast of superficial dermis (De). Co indicates collagen (original magnification ×6200).

1.
de Waard-van der Spek  FBMulder  PGOranje  AP Prilocaine/lidocaine patch as a local premedication for skin biopsy in children. J Am Acad Dermatol 1997;37 (3, pt 1) 418- 421
PubMedArticle
2.
Buckley  MMBenfield  P Eutectic lidocaine/prilocaine cream: a review of the topical anaesthetic/analgesic efficacy of a eutectic mixture of local anaesthetics (EMLA). Drugs 1993;46 (1) 126- 151
PubMedArticle
3.
Hoss  DMGross  EGGrant-Kels  JM Histopathology of an adverse reaction to a eutectic mixture of the local anesthetics lidocaine and prilocaine. J Cutan Pathol 1999;26 (2) 100- 104
PubMedArticle
4.
Dong  HKerl  HCerroni  L EMLA cream-induced irritant contact dermatitis. J Cutan Pathol 2002;29 (3) 190- 192
PubMedArticle
5.
Vallance  HChaba  TClarke  LTaylor  G Pseudo-lysosomal storage disease caused by EMLA cream. J Inherit Metab Dis 2004;27 (4) 507- 511
PubMedArticle
Research Letter
August 2007

Histologic Cutaneous Modifications After the Use of EMLA Cream, A Diagnostic Pitfall: Review of 13 Cases

Arch Dermatol. 2007;143(8):1073-1087. doi:10.1001/archderm.143.8.1074

While the eutectic mixture of lidocaine and prilocaine (EMLA cream; AstraZeneca International, Södertälje, Sweden) is the topical anesthetic most widely used before performing a skin biopsy,1,2 EMLA-induced cutaneous histologic alterations have rarely been reported.35 We herein report 13 cases where pathological diagnosis was highly complicated by EMLA application.

Methods

We reviewed 13 skin biopsy specimens obtained after EMLA application from children (mean ± SD age, 3.6 ± 4.4 years) with erythematous and squamous disease (n = 4, patients 1-4), keratinization disorder (n = 4, patients 5-8), bullous disease (n = 3, patients 9-11), and suspected storage (n = 1, patient 12) or connective tissue (n = 1, patient 13) disorders.

In addition to histopathologic findings in relation to suspected diagnoses, unexpected striking features were observed in 9 biopsy specimens (Figure 1). A diffuse pallor with swollen upper keratinocytes was seen in 7 specimens (patients 1-3, 5, 7, 9, and 10). Lower keratinocytes displayed a sharp vacuolization in 8 cases (patients 1-7 and 10). Destruction of the basal layer was observed in 8 cases (patients 1, 2, 4-7, 9, and 10). Either focal or large subepidermal cleavages were seen in 9 patients (patients 1-7, 9, and 10). In 3 cases (patients 11-13), the skin was found to be normal under standard histologic analysis.

The major ultrastructural feature was the constant vacuolization of keratinocytes occurring in the basal, spinous, granular, and/or horny layers (Figure 2). The second characteristic pattern was a marked enlargement of intercellular spaces leading to stretching or rupture of cellular interdigitations without splitting of desmosomes (n = 1, patients 6, 7, and 9-11). Finally, vacuoles were seen in 7 cases in dermal cells, fibroblasts, and/or the epithelium of sweat glands and hair follicles (patients 6-9 and 11-13). In cases devoid of pathologic features in standard histologic analysis, electron microscopy confirmed the existence of cell vacuoles in the epidermis and/or the dermis.

Comment

We describe 13 patients for whom pathologic findings were not consistent with clinical suspected diagnoses. In most cases, microscopy showed swelling and vacuolization of the upper epidermis and destruction of the basal layer resulting in cleft formation. This intriguing histologic pattern occurring in various types of cutaneous disorders after EMLA application led us to suspect the cream as the cause. Skin sensitivity to EMLA might depend on individual factors such as underlying disease, age, or application protocol. In 3 cases, there was a vacuolization of keratinocytes and dermal cells only patent on ultrathin sections.

Additional skin biopsies from areas not treated with EMLA were performed for 6 patients. Showing none of the previous alterations, these specimens allowed the adequate diagnosis of 1 case of lamellar ichthyosis, 3 cases of hereditary epidermolysis bullosa, and the exclusion of storage disease in one case and Ehlers Danlos disease in another. Our data are in accordance with the few published cases35 and emphasize diagnosis difficulties caused by EMLA in a wide range of cutaneous abnormalities, especially those requiring electron microscopy.

It is important to point out that EMLA-induced histopathologic changes can favor misdiagnosis or prevent ultrastructural analysis. Therefore, dermatologists should always note the use of EMLA cream on the pathology form and, when possible, avoid its use in blistering disorders, interface dermatitis, and connective tissue or storage disorders.

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Article Information

Correspondence: Dr Fraitag, service d’Anatomie Pathologique, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris CEDEX 15, France (sylvie.fraitag@nck.aphp.fr).

Financial Disclosure: None reported.

References
1.
de Waard-van der Spek  FBMulder  PGOranje  AP Prilocaine/lidocaine patch as a local premedication for skin biopsy in children. J Am Acad Dermatol 1997;37 (3, pt 1) 418- 421
PubMedArticle
2.
Buckley  MMBenfield  P Eutectic lidocaine/prilocaine cream: a review of the topical anaesthetic/analgesic efficacy of a eutectic mixture of local anaesthetics (EMLA). Drugs 1993;46 (1) 126- 151
PubMedArticle
3.
Hoss  DMGross  EGGrant-Kels  JM Histopathology of an adverse reaction to a eutectic mixture of the local anesthetics lidocaine and prilocaine. J Cutan Pathol 1999;26 (2) 100- 104
PubMedArticle
4.
Dong  HKerl  HCerroni  L EMLA cream-induced irritant contact dermatitis. J Cutan Pathol 2002;29 (3) 190- 192
PubMedArticle
5.
Vallance  HChaba  TClarke  LTaylor  G Pseudo-lysosomal storage disease caused by EMLA cream. J Inherit Metab Dis 2004;27 (4) 507- 511
PubMedArticle
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