Late Cutaneous Manifestations 14 to 20 Years After Wartime Exposure to Sulfur Mustard Gas: A Long-term Investigation

Sulfur mustard gas (SM) is a potent alkylating agent that has a long history of use as a chemical warfare agent, including recent use by Iraq against Iranian soldiers and civilians.¹ The organs most commonly affected by SM are the skin, eyes, and airways. Skin lesions are seen in more than 90% of the patients exposed to SM. Although the acute systemic² and cutaneous³ effects of SM are well known, few investigations have dealt with the long-term effects.⁴ The aim of this study was to investigate the long-term cutaneous problems experienced by survivors of SM attack several years after exposure.

The 800 male subjects of this cross-sectional descriptive study were recruited from surviving veterans of the Iraq-Iran war (1) whose exposure to SM from 1983 to 1988 was documented in their wartime medical records and (2) who had at least 1 cutaneous sign or symptom at the time of evaluation for this study. The survey was performed 14 to 20 years after exposure of the subjects to SM. Physical examinations conducted for this investigation focused on defining the diagnosis and the extent of the cutaneous disorders among the subjects and their correlation with previous SM exposure. Laboratory investigations including histopathologic studies were carried out whenever clinically indicated.

The clinical data were collected by the cluster sampling method. The frequency of each clinical sign or disease was calculated with 95% confidence intervals, and the final data were statistically analyzed and compared with some available related data in the healthy population^5,6 using the Fisher exact test and SPSS software, version 12 (SPSS Inc, Chicago, Illinois).

The mean (SD) age of the patients was 39.3 (9.8) years (age range, 18-80 years). Almost all of the patients were exposed to SM only once.

The cutaneous signs and disorders could be categorized into 3 different groups (Table). The first group was nonspecific skin disorders (93.4%), including seborrheic dermatitis, eczema, multiple cherry angiomas (Figure 1), and several other conditions. The relationship between frequency of eczema, seborrheic dermatitis, psoriasis, urticaria, vitiligo, and tinea versicolor in study subjects exposed to SM compared with the frequency of these diseases found in a National Health Survey⁵ was statistically significant (Table).

The second group included SM scars (5.5%). These specific lesions developed mainly at the sites of previous SM-induced bullae or infected ulcers. The scars (Figure 2) showed the clinical features of irregular margins, pigmentary changes as localized leukomelanoderma (“salt and pepper” appearance), vascular changes (telangiectasia and cherry angioma), reticular atrophic and hypertrophic areas, islands of normal-appearing skin, and the usual histopathologic features of scars.

Finally, malignant cutaneous neoplasms (1.1%) (skin cancer) were observed in 9 patients: 5 cases of basal cell carcinoma and 1 case each of squamous cell carcinoma, Bowen disease, dermatofibrosarcoma protuberans, and mycosis fungoides (tumoral). In all of these patients except 2 cases of basal cell carcinoma, the skin neoplasm developed on the scar of previous SM-induced lesions. The frequency of nonmelanoma skin cancer in subjects exposed to SM (1.1%) compared with the prevalence generally in Iran (0.01%) reveals statistical significance (Table).⁶

In the present report, we have categorized our findings into 3 groups. The first, nonspecific cutaneous signs and disorders (Table), has already been reported in association with SM exposure as late skin findings.^1,2 However, owing to lack of a control group in the present descriptive study, and also the multifactorial causes of these disorders, correlation of them with exposure to SM could not be confirmed. Nonetheless, the higher incidence compared with the normal population is noteworthy.⁵

We also found SM scars, with their special pigmentary, trophic, and vascular changes, to be specific lesions somehow different from other burn scars. They were usually localized and had ill-defined borders, areas of hyperpigmentation and depigmentation beside each other (localized leukomelanoderma), reticular atrophic and hypertrophic areas with islands of normal-appearing skin, and occasional cherry angiomas and telangiectasia.

Finally, 9 patients in our study developed cutaneous malignant neoplasms several years after SM exposure.⁶ Since SM is an alkylating agent and DNA is one of SM's most sensitive targets, it is not surprising that carcinogenesis and radiomimetic effects were seen. To date, the number of cutaneous cancers reported subsequent to acute and chronic SM exposure is low, and it is unclear whether some of these cutaneous neoplasms are related to the carcinogenic effects of SM or are related to the presence of chronic skin ulcers and scars.²

In conclusion, there maybe a causal relationship between acute and severe exposure to SM and hyperpigmentation, depigmentation, chronic skin ulceration, scar formation (with specific features of pigmentary, trophic, and vascular changes), and development of skin cancer.

Correspondence: Dr Emadi, Behsima Center of Dermatology and Laser Therapy, Shahin Street, Valiasr Avenue, Tehran, Iran (emadi_mortazavi@hotmail.com).

Author Contributions: Drs Emadi and H. Mortazavi had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Emadi and H. Mortazavi. Acquisition of data: Emadi. Analysis and interpretation of data: Emadi, M. Mortazavi, and H. Mortazavi. Drafting of the manuscript: M. Mortazavi. Critical revision of the manuscript for important intellectual content: Emadi, M. Mortazavi, and H. Mortazavi. Statistical analysis: H. Mortazavi. Administrative, technical, and material support: Emadi, M. Mortazavi, and H. Mortazavi. Study supervision: Emadi and H. Mortazavi.

Financial Disclosure: None reported.

Additional Contributions: Hamid Haghani provided statistical advice, and Mohammed Ghasemi Boroomand, MD, Saeed Keshavarz, MD, Shahriar Khateri, MD, Mohammed Araghizadeh, MD, Mohammedreza Soroush, MD, and Amir Hossein Eskandari, MD, provided cooperation and help in performing this study.