Although many drugs are excreted in sweat 1–3, sufficient data on the histopathological involvement of the eccrine sweat apparatus in adverse cutaneous drug reactions (ACDRs) are lacking. To date and to the best of our knowledge, only few related studies have been published 2–6.
The current study aimed at investigating histopathological changes in the eccrine sweat apparatus in lesional and nonlesional skin in various types of ACDRs.
Patients and methods
This cross-sectional study was conducted after obtaining approval from the Departmental Research Ethical Committee and informed consent from patients or parents/guardians for minors. Forty consecutive patients with ACDRs were recruited from the inpatient medical/surgical wards and the Outpatient Dermatology Clinic, Kasr El-Aini Hospital. Medical history and detailed drug history were recorded.
Two punch skin biopsies were obtained from each patient, ensuring sufficient depth to include subcutaneous tissue: a 5-mm lesional skin specimen from a mature lesion (<48 h duration) and a 4 mm specimen from adjacent normal-appearing skin (nonlesional skin). Both biopsies were fixed in 10% neutral buffered formaldehyde, dehydrated, and embedded in paraffin.
For routine hematoxylin and eosin staining 4 µm sections were prepared. Slides were examined for establishment of a histopathological diagnosis. The final diagnosis of each patient was based on clinicopathological correlation (clinicopathological type of ACDR). Detailed histopathological evaluation of all components of the eccrine sweat gland apparatus (acrosyringium, distal duct, proximal duct, and secretory coils) was carried out for routinely stained hematoxylin and eosin sections from both lesional and nonlesional skin biopsies.
Photomicrographs depicting the various changes observed in the sweat apparatus in the studied patients were obtained. All photomicrographs presented are in their original magnification.
Data were encoded and entered using statistical package for the social science (SPSS Inc., Chicago, Illinois, USA), version 18, and Microsoft Excel 2007 (Microsoft Corporation, New York, New York, USA). Data were summarized using mean±SD for quantitative variables and percentage for qualitative variables. Comparisons between groups were carried out using χ2-tests for qualitative variables. P values less than 0.05 were considered statistically significant.
The study included 23 (57.5%) female and 17 (42.5%) male patients. Their ages ranged from 1 to 74 years, with a mean of 39.1±18.85 years.
The clinicopathological types of ACDRs included the following: exanthematous drug reaction [eight (20%) patients], vasculitic drug reaction [six (15%) patients], urticarial drug reaction [four (10%) patients], lymphomatoid drug reaction [three (7.5%) patients], acute generalized exanthematous pustulosis [AGEP; two (5%) patients], Stevens–Johnson syndrome [SJS; two (5%) patients], erythema multiforme [EM; two (5%) patients], drug-induced pemphigus [DIP; two (5%) patients], fixed drug reaction [FDR; two (5%) patients], psoriasiform drug reaction [two (5%) patients], drug reaction with eosinophilia and systemic symptoms [one (2.5%) patient], toxic epidermal necrolysis [TEN; one (2.5%) patient], pityriasiform drug reaction [one (2.5%) patient], pigmented purpuric dermatosis-like drug reaction [one (2.5%) patient], iododerma [one (2.5%) patient], Sweet’s syndrome [one (2.5%) patient], and lichenoid drug reaction [one (2.5%) patient].
Pathological changes in the eccrine apparatus were detected in 39 out of 40 (97.5%) lesional and in 16 out of 38 (42.1%) nonlesional biopsies. The only case that did not show involvement of the apparatus in lesional skin was a case of urticaria. The 16 cases with nonlesional involvement of the apparatus were those with exanthematous drug reaction (four cases), urticaria (three cases), AGEP (two cases), lymphomatoid drug reaction (two cases), psoriasiform drug reaction (one case), SJS (one case), EM (one case), FDR (one case), and DIP (one case).
Eccrine sweat gland changes were significantly encountered in lesional skin compared with nonlesional skin when assessed as a whole (P<0.0001) as well as when assessed in different parts of the eccrine sweat glands apparatus (acrosyringium: P<0.005; distal duct: P<0.0001; proximal duct: P<0.005; and secretory coils: P<0.0001).
Not all biopsies showed all components of the eccrine apparatus despite multiple sectioning. Histopathological changes in the different parts of the eccrine apparatus encountered in lesional and nonlesional skin and along the range of the clinicopathological types of ACDRs are illustrated in Tables 1 and 2, respectively, and in Figs 1–3.
The current study provides insight into histopathological involvement of the eccrine sweat apparatus in ACDRs. Secretory coils were the most affected in lesional skin (89.5%). Their active excretory role 7 and their expression of various cytokine receptors 8 give reason for this high input. Such receptors interact with cytokines produced by inflammatory cells that usually extend to the vicinity of the secretory coils in drug reactions 9. We detected changes in the coils in all cases belonging to the EM/SJS/TEN spectrum, a feature not previously reported 4,5. Interestingly, deeper extension of the infiltrate was found in these cases. Necrosis of secretory epithelium was not found except in a case of AGEP and focally in one case of vasculitis. Secretory coil necrosis has only been reported with drug-induced blisters in comatose patients 10–14 and in one noncomatose patient 2.
Distal ducts, on the other hand, were involved more commonly (87.5%) than proximal ducts (60%), probably reflecting higher proliferative activity 15 and vulnerability to cytokine-mediated damage 5. It may also be speculated that their proximity and direct continuity with the surface epidermis make them more directly influenced by interface changes observed in most drug reactions. Researchers have earlier reported proximal duct involvement only in continuity with that of the distal duct 4,5 and proximal duct dilatation secondary to distal duct damage 4. Necrosis of luminal cells was detected in the distal duct in one of three cases with vascultis, which was characterized by intense neutrophilic infiltrate around the affected duct and severe necrosis of the adjacent vessels. One case of pityriasiform drug reaction also showed luminal cell necrosis, which may be attributed to massive cytokine release. It was seen in the proximal duct only in a case of AGEP, possibly in addition to the cytokine effect. Ductal changes reported in the EM/SJS/TEN spectrum and in FDRs in this series were nearly similar to those reported by others 4,5.
The acrosyringium was the least affected (54.2%). Its involvement appears as a part of the surrounding epidermal pathological changes 4. Acrosyringial necrosis was commonly encountered in the EM/SJS/TEN spectrum, mediated by cytotoxic T lymphocytes inducing variable degrees of epidermal necrosis as previously reported 16,17. Necrotic keratinocytes centered in the acrosyringium have been reported as an indication for drug-induced EM and may be due to drug concentration in sweat with subsequent toxic and immunologic effects 6. A related dermal inflammatory infiltrate containing sparse eosinophils was also seen in our cases of EM as reported by others 6. Acrosyringial necrosis as part of epidermal necrosis was also noted in a patient with drug-induced Sweet’s syndrome and in one case of vasculitic drug reaction, presumably resultant from impediment of blood supply. Apoptotic keratinocytes, reflecting the basic finding in lichenoid tissue reactions 18, were detected in the acrosyringium in the only case of lichenoid drug reaction in this series.
Overall, it appears that lesional skin changes of eccrine sweat glands in ACDRs are secondary to different mediators of the inflammatory process rather than events primarily and directly caused by the inciting drugs.
Sweat glands in nonlesional skin appeared less frequently involved than in lesional skin and were mainly discerned in drug reactions of cell-mediated pathogenic mechanisms and in cases that are widespread in nature, such as exanthematous drug reaction, urticaria, AGEP, lymphomatoid drug reaction, psoriasiform drug reaction, SJS, EM, and DIP, in addition to one case of FDR. In the majority of these cases (13/16, 81.25%), nonlesional skin showed other histopathological features similar to but milder than those encountered in lesional skin. Histopathological involvement of nonlesional skin has been reported in other skin diseases such as mycosis fungoides 19, leprosy 20, and pityriasis versicolor 21. The current study reports such changes in ACDRs and adds to the importance of viewing nonlesional skin as being subclinically affected with liability to progress to overt clinical involvement.
Eccrine sweat glands were significantly involved in lesional skin, with secretory coils being the most affected parts. It appears that pathological changes in eccrine sweat glands in ACDRs are secondary consequences to cytokines and mediators released during inflammation, rather than being primary effects specific to each particular reaction or drug.
Further studies are needed with a larger number of cases in each of the clinicopathological types of ACDRs to draw significant associations between certain histopathological changes and the clinicopathological types of ACDRs. Moreover, comparing sweat gland changes in certain drug-induced eruptions with non-drug-induced similar eruptions may help developing certain clues in the sweat gland apparatus that favor drug origin in such eruptions.
The authors thank all members of the Dermatology Department for their support in collection of cases. They extend a special thanks to Dr Mona El-Lawindi, Professor of Public Health, Faculty of Medicine, Cairo University, for her help in the statistical analysis in this work.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2016 Egyptian Women's Dermatologic Society
adverse cutaneous drug reactions; eccrine sweat glands; histopathological changes