Marjolin's ulcer revisited – basal cell carcinoma arising from grenade fragments? Case report and review of the literature

Case report 

A 79-year-old white male patient presented to our clinic in March 2004 with chronic ulceration over the medial aspect of his left calf. Interview with the patient revealed that he had sustained an injury from grenade fragments in his left calf on D-Day 1944 during World War II. He stated that initially the wound was healing poorly due to an infection. One operation for debridement was necessary back in 1944 and within several weeks after that wound closure was achieved. For the following 56 years the patient had no further problems with his left calf. However, four years prior to presentation to our clinic he had noticed a small ulceration with little discharge over the medial aspect of his left calf. On a couple of occasions he had seen different practitioners and was treated for venous disease.

On presentation we noted an ulcer, 4cm×2cm in size (Fig. 1), with little discharge. As an initial clinical diagnosis the lesion mimicked an irritative ulceration due to a foreign body reaction. On dermatoscopic examination a neoplastic component could not be ruled out and a skin biopsy showed that the lesion was BCC (Fig. 2). Radiography of the lower leg revealed that some of the grenade fragments were still in situ (Fig. 3).

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Figure 1 Clinical presentation of a 79-year-old patient with chronic ulceration over his left calf.

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Figure 2 The BCC reveals acanthotic broadened epidermis (left side). Basalioma consisting of basophilic cell threads with palisaded tumour cells on the right margin (right side). The dermal connective tissue is scarred (magnification 25×).

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Figure 3 X-ray views oft left lower leg; (a) lateral view; (b) anterior–posterior view. Note: grenade fragments (pointing arrows) still in situ in the left calf.

Tumour resection was carried out with 2cm margins and the defect was covered with a split skin graft. The pathological evaluation confirmed the diagnosis of basal cell carcinoma with a completely excised tumour. The post-operative course was uneventful with good wound healing.

Review of literature 

A review of the literature reveals five published cases of grenade fragments left in situ in various parts of the human body associated with development of malignancies (Table 1).18, 19, 20, 21, 22 The association of grenade fragments with development of different kinds of lung cancer has been described in three cases.18, 19, 21 Tolle20 has reported development of basal cell carcinoma of the ethmoid associated with a grenade splinter injury. An Australian group has described the development of angiosarcoma 63 years after an injury to the right axilla from a German stick grenade during World War I. Development of the tumour was seen in relation to several metal grenade fragments which were in proximity as well as within the tumour mass.22

Table 1. Type of neoplasms following grenade fragment injuries, synopsis of authors, years of publication, journals and body location

	Author	Year	Journal	Type of neoplasm	Location in body
	Schutz and Stein18	1956	Thoraxchirurgie	Lung carcinoma	Lung
	Peter19	1966	Zentralbl Allg Pathol	Lung carcinoma	Lung
	Tolle20	1967	HNO	Basal cell carcinoma	Ethmoid
	Stambolis et al.21	1982	Med Welt	Lung-scar cancer	Lung
	Hayman and Huygens22	1983	J Clin Pathol	Angiosarcoma	Right axilla

Tumourigenesis due to a foreign body has been extensively studied in animals and has been reviewed by Brand et al.23 It has been shown that physical presence of implants alone can be responsible for tumourigenesis,23 and even non-reactive materials such as gold, platinum or stainless steel were proven to be tumourigenic in mice or rats provided that the surfaces were intact and continuous. When these surfaces were roughened or softened the tumour incidence decreased markedly.22

In humans foreign body induced tumours are very rare. When looking at tumours induced by foreign bodies not related to warfare, Fehrenbacher et al.24 reported an angiosarcoma of the aorta, arising near a Dacron aortic graft 12 years after insertion.

Analysis of the current literature with focus on influence of warfare on development of skin cancers and soft tissue sarcoma reveals several possible causes in addition to grenade fragments (Table 2).20, 25, 26, 27, 28, 29, 30, 31, 32, 33 BCC, squamous cell carcinoma, malignant melanoma, Bowen's disease and soft tissue sarcoma have all been shown in causal connection with nuclear testing, atomic bombing and radiation in general.25, 26, 27, 30, 32, 33 Association of burns with development of Marjolin's ulcer has already been mentioned.28 Physical injury to skin in general, being either sharp or blunt, has been associated with development of BCC.29, 31

Table 2. Development of different types of skin malignancies after warfare, authors, years of publication, journals and suspected aetiology

	Type of malignancy	Authors	Year	Journal	Aetiology
	Malignant	Muirhead et al.25	2004	J Radiol Prot	Nuclear testing
	Melanoma	Fink and Bates26	2005	Radiat Res	Atomic bombing
		Kishikawa et al.27	2005	Int J Cancer	Atomic bombing
		Kowal-Vern and Criswell28	2005	Burns	Burn
	Basal cell	Tolle20	1967	HNO	Grenade fragments
	Carcinoma	Noodleman and Pollack29	1986	J Dermatol Surg Oncol	Burn, sharp and blunt trauma
		Nelson and Randle30	2003	Dermatol Surg	Nuclear testing
		Ozyazgan and Kontas31	2004	Scand J Plast Reconstr Surg Hand Surg	Physical skin injury
		Cognetta et al.32	2005	J Am Acad Dermatol	Cathode ray oscilloscope exposure World War II
		Kishikawa et al.27	2005	Int J Cancer	Atomic bombing
		Kowal-Vern and Criswell28	2005	Burns	Burn
		Bauer et al.33	2005	Radiat Res	Nuclear testing
	Squamous	Muirhead et al.25	2004	J Radiol Prot	Nuclear testing
	Cell	Kishikawa et al.27	2005	Int J Cancer	Atomic bombing
	Carcinoma	Kowal-Vern and Criswell28	2005	Burns	Burn
		Bauer et al.33	2005	Radiat Res	Nuclear testing
	Bowen's disease	Kishikawa et al.27	2005	Int J Cancer	Atomic bombing
	Soft tissue	Kowal-Vern and Criswell28	2005	Burns	Burn injuries
	Sarcoma	Muirhead et al.25	2004	J Radiol Prot	Nuclear testing
		Kishikawa et al.27	2005	Int J Cancer	Atomic bombing
		Bauer et al.33	2005	Radiat Res	Nuclear testing

Discussion 

BCC is the most common cancer in humans.34 Exposure to ultra-violet (UV) radiation from sunlight is thought to be a common aetiologic risk factor for BCC as well as other skin malignancies. Although uncommon, an association between skin trauma, a chronic and inflammatory process, and scar formation has been suggested as playing a role in some skin cancer pathogenesis.35 Marjolin's ulcer is described as squamous cell carcinoma and rarely as BCC arising in areas of chronically non-healing wounds.3, 4 These lesions are frequently overlooked and often inadequately treated, as in the case described, when the patient was treated with ointments for four years with no biopsies taken.

Short-term effects from hand grenade injuries have been evaluated in detail36 and biophysics and patho-physiology37 have been studied. Reports of long-term effects of grenade fragments include a large bowel perforation 16 years after injury,38 development of a psoas muscle abscess,38 a brain abcess 47 years after head injury related to metal fragments39 and biliary obstruction secondary to a shrapnel 44 years after injury40 has been reported as well.

Small fragment wounds have been studied in an animal model.37 This study concludes that with small fragments in soft tissue, mainly in subcutaneous tissue, surgical exploration, debridement, excision of dead tissue and delayed primary closure may not be the best treatment option as timely use of antibiotics and leaving of the small fragments in situ yields similar wound healing results with so far no disadvantages.37 However, long-term effects of grenade fragments left in subcutaneous tissue have not been studied in humans so far and case reports are rare. We know that hand grenades and explosives in general contain dozens of substances that have possible mutagenic and tumourigenic potential (Table 3).41 It is generally accepted that arsenic can lead to development of BCC with a lag of 30 years after exposure.22 This mutagenic potential in grenade fragment injuries may hardly count in the short term, but in the long term we think that by leaving the grenade fragments in situ, the mutagenic effect of these substances can work on the surrounding soft tissue for the years to come. In this particular case we think that a couple of factors contributed to the development of BCC including an initial burn component from the hot grenade fragments and secondary wound healing after the trauma. The tumour may also have arisen due to a foreign body reaction as described in the aforementioned animal model.23 Considering that the grenade fragment surfaces can be looked on as not intact or not continuous, the animal model allots reduced tumourigenic potential to the grenade fragments. Thus the influence of impurities with tumourigenic and mutagenic potential diffusing from the grenade fragments seems important.

Table 3. Hazardous potential of explosives, additives to explosives and subsequent products (after Blumes41)

	Effect on health	Explosive materials	Ignition materials	Additives
	No toxic effect	Nitrocellulosis
	Detrimental to health	o-, p-Nitrophenol	Pb-trinitroresorcinate	Phthalates
			Pb-acid, Pb-ipicrate
	Poisonous	Hexogen (RDX), octogen (HMX), 2,4,6-trinitrotoluol, dinitrotoluol, tetryl, 2,4-dinitrophenol, 4,6-dinitro-o-cresol, picrinacid, 1,4-diaminobezol, p-nitroanilin
	Very poisonous	Nitrogylcerine, hexyl, 1,3,5-trinitrobenzol, glycoldinitrate, 1,3-dinitrobenzol
	Neurotoxic		Tetrazen
	Tumourigenic	Hydrazine, o-toluidine, nitrosamine, 2,4-dinitrotoluol, 2,6-dinitrotoluol, 2-amino-4-nitrotoluol, 2,4-diaminotoluol, 2,4,6-trinitrotoluol		N′, N′-diphenylnitrosamin, dioctylphthalate
	Mutagenic	Dinitrotoluols, 2,4,6-trinitrotoluol, 1,3- and 1,5-dinitro-naphthaline, 2-amino-4-nitrotoluol, 2,4-dinitroanisol, 4,6-dinitro-o-cresol, p-nitroanilin, o-nitrotoluol

However, the association of the tumour with the fragments may, of course, be purely coincidental, although this would appear unlikely.

In this case we present a 79-year-old patient with Marjolin's ulcer 61 years after a grenade injury with a histopathologic diagnosis of basal cell carcinoma. Both, BCC as a form of Marjolin's ulcer and grenade fragments as potential aetiology for cancer are rare characteristics in this case. This observation seems to be important in the context of rising conflicts e.g. in the middle east and the continuing use of explosives, such as land mines.42 Many victims have suffered from metal fragment injuries in the last decades and we need to be aware that there might be also a late component of the injury involving tumour development from lost fragments that needs to be addressed.

Therefore we suggest that removal of projectile fragments from soft tissue should be taken into account even if there may no acute life danger be involved, because in our opinion development of BCC after long lasting war injury should be considered as associated disease.