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Occurrence of Mycosis Fungoides in an Iranian Chemical Victim of the Iran--Iraq War with a Long-term Follow-Up: A Case Report and Review of Literature.

Introduction

The etiology of mycosis fungoides (MF) has largely remained unknown. Genetic, immunological, and environmental factors all have been proposed. (1) There has been controversy surrounding the relationship between environmental or industrial exposure and ensuing MF. (2) Regarding the pathophysiology of MF and cutaneous T-cell lymphoma, antigenic stimulation was first proposed more than 20 years ago. (3)

In the following section, a patient with MF in the wake of exposure to sulfur mustard (2,2'-dichloroethyl sulfide) is introduced.

A clear history of exposure to sulfur mustard gas, progression of inflammatory lesions to MF, and long-term follow-up of the patient (>20 y) are the novelties of the present case report. Additionally, the diagnosis of MF was confirmed by histopathology, immunohistochemistry, and the TCR-[gamma] gene rearrangement.

The aim of this study was to highlight sulfur mustard as an environmental risk factor for the development of MF, in support of the antigenic stimulation theory.

Case Report

In September 2015, a 45-year-old man, a known case of MF, was admitted to Razi Hospital, Tehran, Iran, due to the worsening of his skin lesions. He was a victim of chemical weapons in 1987 during the Iran--Iraq war (previously he had been admitted to Razi Hospital several times). He had developed skin lesions 3 years after exposure to sulfur mustard at the age of 21. His skin lesions were on the posterior distal part of his calf, where it was involved with bulla in 1987. The course time between his exposure and diagnosis was 7 years (1994). By that time, he had developed more patches and plaques on his upper and lower extremities, trunk, and abdomen (figure 1a and 1b).

He had undergone 120 sessions of narrowband UVB in total and had been on acitretin (Neotigason[R]) capsules (25 mg/d) and topical steroid for the preceding 4 years before this admission.

Moreover, in his previous admission, there was an erythematous plaque with alopecia on his left eyebrow. A punch biopsy specimen was obtained from his eyebrow lesion, which rendered diffuse infiltration of atypical lymphocyte cells with some convoluted nuclei and scant cytoplasm admixed with lymphocytes, histiocytes, and mast cells compatible with the nodular stage of MF. Immunohistochemistry revealed CD3+, CD4+, and CD7 (-).

On his last admission, there was no lymphadenopathy or hepatosplenomegaly. The liver function test, complete blood cell, and thyroid function test were normal. The human T-cell lymphotropic virus 1 (HTLV-1) test was negative. Computed tomography scan of the thorax, abdomen, and pelvic was normal. A biopsy was obtained from a plaque lesion, which had appeared recently on his left thigh. Histopathological examination revealed marked epidermotropic haloed lymphocytes linearly aligned along the basal layer with blurred dermoepidermal junction and scant spongiosis (figure 2). High-power images of the epidermis showed medium-sized lymphocytes with cerebriform nuclei arranged in Darier's nests (Pautrier's microabscess) (figure 3a). Within the dermis, a dense infiltration of small-to-medium sized pleomorphic lymphocytes with cerebriform nuclei was seen (figure 3b). An additional finding of these biopsies showed the involvement of the follicles by pilotropic small-sized pleomorphic lymphocytes. No mucin deposition within the follicles (follicular mucinosis) was seen (figure 3c). Also, eccrine gland involvement was seen by the infiltration of lymphocytes arranged predominantly around and within the eccrine glands with syringometaplasia (figure 3d). Histopathological findings were consistent with MF with folliculotropism and eccrinotropism (adnexotropism).

The TCR-[gamma] gene rearrangement of the paraffin block of the plaque lesion revealed positive monoclonality. A bone-marrow aspiration was also obtained from the patient. A microscopic examination of the bone marrow specimen revealed no Sezary cell.

The clinical features of the patient, microscopic findings of the lesions, and result of the TCR-[gamma] gene rearrangement were supportive of a diagnosis of MF. The dose of acitretin was increased to 50 mg/d at the last admission and psoralen and ultraviolet A (PUVA) therapy was started. We obtained the patient's consent to report the case.

Discussion

We herein introduced a patient with an established diagnosis of MF. He had a history of exposure to sulfur mustard 3 years prior to the diagnosis of MF. Sulfur mustard is a powerful vesicant chemical warfare agent. (4,5) The toxic effects of sulfur mustard, as an alkylating agent, are exerted through several mechanisms, including DNA alkylation, NAD depletion, and inactivation of glutathione. (5) The 3 major targets of the toxic effects of sulfur mustard are the skin, eye, and respiratory system. (5) The carcinogenicity of sulfur mustard has been verified, and an increased incidence of the upper respiratory tract and cutaneous malignancies following occupational exposure to sulfur mustard has been reported. (6)

The most common type of cutaneous T-cell lymphoma is MF, which accounts for half of all primary cutaneous lymphomas. The incidence of MF is about 0.4 in 100,000 per year in the United States. (1) Men are affected twice as often as women. The mean age of the affected patients at the time of diagnosis is between 55 and 60 years. (1)

The etiology of MF has largely remained unknown. Genetic, immunological, and environmental factors all have been proposed. (1) There has been controversy surrounding the relationship between environmental or industrial exposure and ensuing MF. (2) In 1979, Fischman and colleagues (7) studied the history of exposure to chemical, biological, and physical agents in patients with cutaneous T-cell lymphoma, including MF and the Sezary syndrome. The authors showed that a high percentage of their patients had a history of chemical exposure. Researchers have also demonstrated that exposure to aromatic and/or halogenated hydrocarbons could be associated with MF and hypothesized that job exposure could be an etiological factor for the appearance of MF. (8) In a recent publication, the development of the Sezary syndrome, namely the erythrodermic stage of MF, in a victim of chemical weapons during the Iran--Iraq was reported. (4) MF has an indolent course with a protracted progression from patch stage to plaque, tumor, and visceral involvement. It may take many years or sometimes even decades before a definite diagnosis. (9) The immunophenotype of neoplastic cells in MF shows CD3+, CD4+, CD45RO+, and CD8-. (7) A minority of the patients exhibit CD3+, CD4-, and CD8+ without any clinical and prognostic differences. (10)

According to the antigenic stimulation theory, long-term stimulation of lymphocytes could lead to the transformation of lymphocytes to T-cell lymphoma with low-grade malignancy. (3) In addition, Burg and colleagues (11) showed that chronic inflammation through long-term antigenic stimulation could give rise to neoplasia. A case-control study as well as mutation gene analysis showed that sun exposure, as an environmental factor, could be a contributing factor in the development of MF. (8,12) In the case presented herein, sulfur mustard may have led to the inflammation of skin and eczematous lesions. Subsequently, the chronic inflammation of the skin may have resulted in chronic antigenic stimulation. Finally, the above-mentioned process may have resulted in the development of MF.

Conclusion

The progression of inflammatory lesions to MF, a type of cutaneous T-cell lymphoma, showed that chronic inflammation and consequently, chronic antigenic stimulation could lead to neoplasia. At least, sulfur mustard could be a risk factor for the development of MF, presumably through antigenic stimulation.

Conflict of Interest: None declared.

References

(1.) Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol. 2007;143:854-9. doi: 10.1001/archderm.143.7.854. PubMed PMID: 17638728.

(2.) Moreau JF, Buchanich JM, Geskin JZ, Akilov OE, Geskin LJ. Non-random geographic distribution of patients with cutaneous T-cell lymphoma in the Greater Pittsburgh Area. Dermatol Online J. 2014;20. PubMed PMID: 25046454.

(3.) Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D. Rook's Textbook of Dermatology, 4 Volume Set. New York: John Wiley & Sons; 2016.

(4.) Emadi SN, Babamahmoodi F, Poursaleh Z, Sayad-Noori SS, Soroush MR, Maleki AR, et al. Sezary syndrome, Kaposi sarcoma and generalized dermatophytosis 15 years after sulfur mustard gas exposure. J Dermatol Case Rep. 2012;6:86-9. doi: 10.3315/jdcr.2012.1109. PubMed PMID: 23091586; PubMed Central PMCID: PMCPMC3470796.

(5.) Balali-Mood M, Mousavi S, Balali-Mood B. Chronic health effects of sulphur mustard exposure with special reference to Iranian veterans. Emerg Health Threats J. 2008;1:e7. doi: 10.3134/ehtj.08.007. PubMed PMID: 22460216; PubMed Central PMCID: PMCPMC3167581.

(6.) Goverman J, Montecino R, Ibrahim A, Sarhane KA, Tompkins RG, Fagan SP. Sulfur mustard gas exposure: Case report and review of the literature. Ann Burns Fire Disasters. 2014;27:146-50. PubMed PMID: 26170794; PubMed Central PMCID: PMCPMC4441314.

(7.) Fischmann AB, Bunn PA, Jr., Guccion JG, Matthews MJ, Minna JD. Exposure to chemicals, physical agents, and biologic agents in mycosis fungoides and the Sezary syndrome. Cancer Treat Rep. 1979;63:591-6. PubMed PMID: 445514.

(8.) Morales-Suarez-Varela MM, Olsen J, Johansen P, Kaerlev L, Guenel P, Arveux P, et al. Occupational sun exposure and mycosis fungoides: A European multicenter case-control study. J Occup Environ Med. 2006;48:390-3. doi: 10.1097/01.jom.0000194160.95468.20. PubMed PMID: 16607193.

(9.) van Doorn R, Van Haselen CW, van Voorst Vader PC, Geerts ML, Heule F, de Rie M, et al. Mycosis fungoides: Disease evolution and prognosis of 309 Dutch patients. Arch Dermatol. 2000;136:504-10. PubMed PMID: 10768649.

(10.) Tosca AD, Varelzidis AG, Economidou J, Stratigos JD. Mycosis fungoides: Evaluation of immunohistochemical criteria for the early diagnosis of the disease and differentiation between stages. J Am Acad Dermatol. 1986;15:237-45. PubMed PMID: 3528242.

(11.) Burg G, Kempf W, Haeffner A, Dobbeling U, Nestle FO, Boni R, et al. From inflammation to neoplasia: New concepts in the pathogenesis of cutaneous lymphomas. Recent Results Cancer Res. 2002;160:271-80. PubMed PMID: 12079224.

(12.) McGirt LY, Jia P, Baerenwald DA, Duszynski RJ, Dahlman KB, Zic JA, et al. Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood. 2015;126:508-19. doi: 10.1182/blood-2014-11-611194. PubMed PMID: 26082451; PubMed Central PMCID: PMCPMC4513251.

Hossein Mortazavi (1), MD;

Leila Izadi Firouzabadi (1), MD;

Alireza Ghanadan (2), MD;

Hassan Seirafi (1), MD;

Seyed Naser Emadi (1), MD;

Safoura Shakoei (3), MD

(1) Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran;

(2) Department of Pathology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran;

(3) Department of Dermatology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran

Correspondence: Safoura Shakoei, MD; Department of Dermatology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Postal Code: 14197-33141, Tehran, Iran

Tel: +98 21 61192655

Fax: +98 21 88046767

Email: dr.shakoei@gmail.com

Received: 08 December 2016

Accepted: 05 February 2017

What's Know

* Etiology of mycosis fungoides (MF) has largely remained unknown. Genetic, immunological, and environmental factors all have been proposed. There has been controversy about the relationship between environmental exposure and MF.

What's New

* Clear history of exposure to sulfur mustard gas, progression of inflammatory lesions to MF, and long-term follow-up of the patient (> 20 y) are the novelties of this case report. Additionally, the diagnosis of MF was confirmed by histopathology, immunohistochemistry, and TCR-[gamma] gene rearrangement.
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Article Details
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Title Annotation:Case Report
Author:Mortazavi, Hossein; Firouzabadi, Leila Izadi; Ghanadan, Alireza; Seirafi, Hassan; Emadi, Seyed Naser
Publication:Iranian Journal of Medical Sciences
Article Type:Case study
Geographic Code:7IRAN
Date:May 1, 2018
Words:1821
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