Review of Marjolin Ulcer

7/29/2019 Review of Marjolin Ulcer

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A REVIEW OF MARJOLIN’S ULCER

SUMMARY

Marjolin’s ulcer is an occasional form of cutaneous cancer

seen in our environment. Owing to the behaviour of the

lesion and late presentation the treatment results are often

disappointing.

A review of relevant literature based on a medline search

was made and is here presented in the context of our local

environment.

Key words: Marjolin’s ulcer, squamous cell carcinoma, late

presentation

Introduction

Marjolin’s ulcers are epidermoid carcinomas developing in

non-healing scar tissue.1

Clinical studies of Marjolin’s ulcers

have been done in the United Kingdom, 2 Korea, 3 and United

States of America 4 over a decade ago.

Regional differences in epidemiology are recognised.2



The leading aetiology of the ulcer world-wide is a post-burn

wound.

In contrast that had not been the leading cause in our

environment.5 The incidence appears on the increase and

outcome of treatment poorer.

Materials and Methods

A review of relevant literature based on a medline search

was made and is here presented in the context of our local

environment.

Discussion

The association between thermal burn scars and neoplasia

was initially recognized by Celsus in AD 100.6 Tumours

occurring in burn scars of long duration were reported by J.N.

Marjolin in 1828, but it was Dupuytren who noted it was a

malignancy.7 Da Costa in 1903 first coined the term

"Marjolin's ulcer", applying it to tumours arising in simple leg

ulcers. 8 The term Marjolin’s ulcer may be applied to any



cutaneous carcinoma arising in a cicatrix. Marjolin’s ulcers

are still regarded as rare tumours by some Nigerian workers

9

but this view is most probably due to under reporting.

Other workers in Africa and Europe 10, 11 have reported it is

not rare, and some Nigerian workers report the lesion

represents up to 30% of all primary skin cancers seen in our

environment. 5

Predisposing lesion

The most frequent predisposing lesion is a post burn

wound.3, 12 The cause is frequently flame burns, but electrical

burns and other thermal burns have been reported. 3, 4, 13 That

had not been so in this environment; post traumatic ulcers

have been noted to be a commoner pre-existing lesion by

some Nigerian workers.5 Marjolin’s ulcers have also been

reported following other traumatic injuries, leg ulceration,

chronic sinuses of osteomyelitis, pressure sores, and discoid

lupus erythematosus.14 They have also been documented in

the genitalia as a complication of Fournier’s gangrene. 15

Sites of predilection



Marjolin’s ulcers are most commonly found in the lower limbs.

Occasionally they occur around the upper limbs, head region and the trunk

in that order. 4, 5, 12, 16 The average percentages are: The lower extremities

(43.7%), upper extremities (22.4%), trunk (11.5%) and head (22.4%). 17

When they occur in post burn contractures they are often

around the region of maximum tension which undergoes

repeated breakdown such as the popliteal fossa and cubital

fossa.

Epidemiology

Even though chronic leg ulcers are more common in females, in all

geographic locations Marjolin’s ulcers are more common in

males.3, 5, 18, 19 In Nigeria the male/female ratio of 1.4: 15

appears closer than the findings of 3:1 in Korea 3 and India,19

but is similar to a recent study in Turkey.17 As in other

locations 3, 4, 12 the lower limb is the commonest site in

Nigeria. 5, 16 The mean ages in previous studies have been 50

years, 3 58 years, 20 and 59 years. 4

Current findings in Africa

10, 21 suggest the mean age is lowering. In Nigeria a mean of

43 years was reported in 1987.5 Marjolin’s ulcer appears to

be affecting younger patients over the years. It also appears



the transition time is getting shorter. The earliest age at

presentation and the transition time are definitely lower now

than the finding in the same environment over a decade ago5 judging by recent studies elsewhere in Africa. 10

It has

earlier been noted that Marjolin’s ulcer affects Nigerians of a

younger age group and shows a shorter transition time. 16

The transition time is quite variable depending on the study

reviewed, and has varied from three months 3 to 63 years. 6,

22 Up to 67 years has been reported. 21 When the transition

time is less than one year the term “acute Marjolin’s ulcer”

has been used. Its transition time ranges from four weeks to

one year with an average of four months. The chronic type is

seen after one year with an average transition time of 36

years.17 When the predisposing lesion is a pressure sore

shorter transition times averaging 25 years7 are noted.

Acute scar carcinoma is regarded as a rare phenomenon.6

Inappropriate treatments of ulcers with irritants can only

shorten the transition time. The practice of native

medication for many leg ulcers may worsen the outcome in

our environment. Many of the patients come when the lesion



is florid and incurable (figure 1). These observations make

Marjolin’s ulcers an urgent concern to the clinician in Nigeria.

Aetiology

The aetiology is not quite clear, but is believed to be multifactorial. Chronic

irritation and the induction of a constantly proliferating epidermal unit

following slow healing and scar instability have been blamed.6 Even though

the usual pattern is repeated cycles of healing and break down, malignant

transformation also occurs in wounds that never healed.18 Another factor is

reduced vascularity and depigmentation in scars. The authors note unstable

scars are frequently depigmented in wounds healing by secondary intention.

It has been postulated these result in a reduced ability to withstand

carcinogens.6, 19 The relatively avascular scar tissue may then

act as an immunologically privileged site that allows the

tumor to resist the body’s usual defenses against foreign

cells. 23 It has been suggested the rich vascularity of the scalp is responsible

for the relatively low incidence of Marjolin’s ulcer presenting there. 24

Marjolin’s ulcer appears quite aggressive in patients with human

immunodeficiency virus. 25

The role of ultraviolet rays in the aetiology of squamous cell cancer is

established. Marjolin’s ulcers are least frequently found on the trunk 4, 5, 17



which is not frequently exposed to sunlight. The principal cause of sun

damage is ultraviolet irradiation at wavelengths between 320 nm and 290

nm (UVB). Upon histologic examination of sun-damaged skin, dyskeratotic

and vacuolated keritinocytes known as sunburn cells are seen. There is also a

reduction in the number of Langerhans cells and a general

immunosuppressive effect. 26 Langerhans cells play a crucial part in the

recognition and presentation of tumour-associated antigens and in cutaneous

immunosurveillance against incipient neoplasms. 27

Alterations in the p53 tumour suppressor gene play a role in the aetiology.

The gene appears to function mainly to guard against irreparable DNA

damage by signalling for apoptosis of critically mutated, precancerous cells

in various tissues and organs, particularly endothelial cells. 28 If mutated or

lost, appropriate DNA repair and/or apoptosis do not occur as cells cycle,

and mutated daughter cells are subsequently selected for clonal expansion.

Mutations of the gene have been commonly found in a variety of human

cancer cells. In particular, recent studies have shown that p53 gene

abnormalities exist in a substantial percentage of squamous cell carcinomas

of human skin. The abnormalities were induced by ultraviolet radiation. 29

The majority of p53 gene abnormalities, perhaps 90%, are missense

mutations that result in an abnormal or truncated protein product of the gene



that typically results in over expression of a non functional p53 protein. 30 A

case study however notes complete absence of the gene in the tumour of a

patient with Marjolin’s ulcer. 31 This may be the reason for its aggression.

Development of squamous cell carcinoma in Marjolin ulcer bears striking

similarity to Huriez syndrome. 4 This rare autosomal dominant

genodermatosis is associated with up to 13% risk of developing cutaneous

malignancies. 32 Immunohistochemical and ultrastructural studies of

involved skin in this syndrome reveal marked reduction in, and occasionally

absence of Langerhans cells.32, 33 It has been noted earlier that sunburns lead

to a reduction in the Langerhans cell population of affected skin. 26

Presentation

They commonly present as non healing ulcers in a post burn

or other post traumatic wounds. It has been postulated the

latent period is inversely proportional to the age the scar

occurred. 2 This is consistent with findings in our

environment.5 A history of a non healing ulcer of up to three

month’s duration should alert the clinician, as well as

wounds with a history of instability, and full thickness burn

wound with bone at the base and little or no soft tissue

intervening.



Two clinical types of Marjolin’s ulcer are present: 17

(1) the flat, indurated, infiltrative, ulcerative carcinoma, and

(2) the exophytic papillary form which is infrequent and

generally less severe. The well-differentiated exophytic

lesions have a better prognosis than poorly differentiated,

ulcerated and infiltrating forms. Typically the edge of the

ulcerated lesion is everted and the floor has poor granulation

tissue.

Marjolin’s ulcers are often described as being painless. It has

been noted that unprovoked bleeding, offensive discharge

and increasing pain are sometimes associated with the ulcer;

either alone or in combination from the tumour. 2 Sometimes

they are due to infection but in the absence of other clinical

signs of inflammation as warmth and erythema, increasing

pain and bleeding probably indicate the tumour has escaped

the confines of the scar. Bleeding from the primary lesion is

associated with recurrent disease, even in the absence of

clinically positive nodes. 3, 17 We recommend that such lesions be

regarded as having escaped the confines of the scar.



Adenopathy may also be present, either following infection

of the ulcer or lymph node metastasis. In late stages with

bony involvement the patient may present with pathologic

fractures.5 Other signs of the initial lesion will also usually be

present, such as skin dyschromias in burn wounds, the tell-

tale signs of venous ulcers, discharging sinuses of

osteomyelitis, pressure sores, etc.

Metastasis

The tumour is initially confined to the scar. At this stage the growth is slow

and it can be completely cured. Once it breaks free of the scar it metastasises

rapidly via the regional nodes. 34 Squamous cell carcinoma resulting from

Marjolin’s ulcer has a greater tendency to metastasise than squamous cell

carcinoma arising from sun damaged skin once it breaks free of the scar. 17

The rate of metastasis is greater (up to 60%) where the predisposing lesion is

a pressure ulcer, than if it arose in a post burn wound (up to 34%).7

Although regional lymph nodes are the most frequent sites

of metastasis, liver, lung, brain, kidney and other distant

metastases also occur. 17 Distant metastases appear earlier

in degenerate sinuses and ulcers than in scars since the



sinuses provide a ready route of spread once neoplastic

changes have occurred.

Diagnosis

This is done following a biopsy which may be excisional, or

incisional for large fungating lesions. Poor sampling by

inexperienced surgeons may result in a delay in diagnosis

when incision biopsy is used in early lesions. A delay in

preparing and reading histology samples, so common in our environment

does not help matters.Even though the histologic type is mostly

squamous cell carcinoma; occasionally other epidermoid

malignancies have been reported. In order of decreasing

frequency they include basal cell carcinoma, malignant

melanoma 5, 6, 18 as well as baso-squamous carcinoma. 35 Non-

epidermoid malignancies reported from burn scars include

fibrosarcoma and adenocarcinoma, 6 liposarcoma, 36

and

osteogenic sarcoma.37 On histology individual keratinisation

of mitotic cells, or cell nests are seen (figure 2).

The features are characteristic. 38 The nests are characterized by

the presence of a basal cell layer and a stratum spinosum which is a

distinctive and diagnostic feature of squamous cell carcinoma. Another



diagnostic feature is the formation of "keratin pearls", concentric

accumulations of keratin at the centers of dysplastic nests of squamous cells.

The level of differentiation may extend quite widely with perfectly benign

appearing nests lying in the dermis to extremely anaplastic cells. In well-

differentiated squamous cell carcinoma the neoplastic squamous cells are

still similar to the normal squamous cells, but are less orderly. The normal

squamous epithelium merges into the squamous cell carcinoma, which

infilterates downward (figure 3). The cells are polygonal in shape with

intercellular bridges. These are seen as desmosomes or "tight junctions" by

electron microscopy (figure 4). However, the neoplastic cells show

pleomorphism, with hyperchromatic nuclei (figure 5).

Staging

The Classification Criteria follows the non melanoma skin

cancer classification by UICC (1997) 39

T - Primary Tumour (physical examination)

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

Tis Carcinoma in situ

T1 Tumour 2 cm or less in greatest dimension

T2 Tumour more than 2 cm but not more than 5 cm in greatest dimension



T3 Tumour more than 5 cm in greatest dimension

T4 Tumour invades deep extradermal structures, i.e., cartilage, skeletal

muscle, or bone

In the case of multiple simultaneous tumours, the tumour with the highest T

category is classified and the number of separate tumours is indicated in

parentheses, e.g., T2(5)

N - Regional Lymph Nodes (physical examination and imaging)

The regional lymph nodes are those appropriate to the site of the primary

tumour.

NX regional lymph nodes cannot be assessed

N0 no regional lymph node metastasis

N1 regional lymph node metastasis

M - Distant Metastasis (physical examination and imaging)

MX distant metastasis cannot be assessed

M0 no distant metastasis

M1 distant metastasis

Treatment

There is as yet no consensus on the protocol of managing Marjolin’s

ulcers.17 The task can be quite difficult as the tumour is

typically aggressive.4, 13 Early recognition offers the best

chance for cure and wide local excision alone in early lesions



may be curative 4, 40 since at this stage it is confined to the

scar. A margin of 3-5 cm is advocated for R 0 clearance.15 Following

excision split skin grafts are preferred to cover the defect.

This aids early detection of recurrence. However when vital

structures are exposed a flap may be preferred, but close

monitoring and nodal status are very necessary if a flap is to

be used as easy venous access to systemic spread is

provided by the flap in recurrence. Controversy exists

regarding the place and timing of lymph node biopsy.1

Sentinel lymph node biopsy has been shown to give as high

a yield as 83% 41 and is recommended to detect occult nodal

involvement. This is advocated in our environment. Once the

sentinel node biopsy is positive the lesion is late.

In late lesions multimodal therapy combining surgery,

chemotherapy and radiotherapy is advocated. 17 This may be in the

form of adjuvant or neo adjuvant therapy.15

Chemotherapeutic agents in use include 5-FluoroUracil,

Methotrexate, Bleomycin and Cisplatinum. 5, 15, 17 Results of

managing late lesions are very disappointing worldwide.



Aggressive therapy is particularly required in scalp lesions as

the outcome appears poorer than other sites. 5, 17

Adjuvant radiotherapy and combination chemotherapy in the form of four

courses of (Methotrexate, Bleomycin and Cisplatinum) is also recommended

to achieve a better disease free survival. 15 Radiotherapy and

chemotherapy using 5 – FluoroUracil have also been tried for

patients unfit for or refusing surgery, all with poor results. 5,

17

Even though chemotherapy and radiotherapy are frequently used for

advanced disease, questions have arisen concerning their usefulness in

Marjolin’s ulcer. 42 Indications for radiation therapy include11

(1) patients with inoperable regional lymph node metastasis

(2) patients with high grade lesions with positive lymph nodes after regional

lymph node dissection

(3) patients with tumor diameter greater than 10 cm, with positive lymph

nodes after regional lymph node dissection,

(4) patients with high grade lesions, with tumor diameter greater than 10 cm

and no positive lymph nodes after regional lymph dissection,

(5) patients with lesions of the head and neck, with positive lymph nodes

after regional lymph node dissection.



Recently gene therapy has shown some promise. 43 Delivery of

wild-type p53 to a radiation-resistant squamous cell carcinoma of the head

and neck cell line was able to reverse the radiation resistant phenotype of

these cells in vitro. The reestablishment of p53 function in these tumor cells

in vitro restored the apoptotic pathway, resulting in a significant increase in

radiation-induced apoptosis that was directly proportional to the level of

exogenous p53 in the tumor cells. More significantly, intravenous

administration of p53 markedly sensitized established squamous cell

carcinoma nude mouse xenograft tumors to radiotherapy. The combination

of systemic p53 gene therapy and radiation resulted in complete tumor

regression and inhibition of their recurrence even 6 months after the end of

all treatment. These results indicate that p53 gene therapy, when used in

concert with conventional radiotherapy, can provide a new and more

effective means of cancer treatment. These are yet to reach Nigeria.

Late presentation is very common in Nigeria.16 In a Korean

study it is associated with a metastasis rate of up to 31.5%. 3

As in Korea, 3 lateness in recognition in Nigeria is often due

to delayed visits to appropriate health facilities on the part of

the patient. 5, 16 Amputation is necessary for late cases with

bone involvement, 3, 5, 20 (especially in the presence of



pathologic fracture). It is the preferred treatment when the

predisposing lesion is a chronic sinus of osteomyelitis

because the tumour cells tend to advance along the sinus

tract early in the disease making adequate local control

difficult. 40 In our environment the amputation rate is high

owing to late presentation, and a number default; refusing

amputation.5, 16 Late presentation is common in the West African

subregion as a result of poverty, ignorance, and poor referral systems in a

relatively expensive health care system devoid of meaningful health

insurance.

The finding of a large lesion associated with foul odour, pain,

or bleeding should alert the clinician of a potentially

advanced lesion. Aggressive management is advocated

particularly for such with close follow up because of the high

incidence of progression/recurrence likely to be associated

with them.

Early recurrence and death within 6 months have been reported.2 Re

excision, radiotherapy, and adjuvant chemotherapy are in use to manage this,

but the outlook in recurrent disease is poor. Most succumb within 2 years. 17

A 1 year disease free interval is associated with a good outcome and a 3 year



disease free interval may be regarded as curative. With such an outlook,

every effort should be geared at prevention.

Prevention

The main stay of prevention is adequate treatment of scars,

particularly those prone to trauma and instability. Often

excision and skin grafting is the mainstay of treatment for

contracting scars but cases of malignant transformation in

wounds previously excised and grafted are reported in

literature. 3, 37, 44 This probably does not include burn wounds

that had early excision and immediate cover with split skin

grafts. Malignant transformation in burn wounds so treated

has not been recorded. The finding of malignant

transformation in ulcers previously excised and grafted calls

to question the adequacy of this mode of treatment used in

isolation particularly in ulcers forming in contractures over

mobile joints, which are prone to repeated stresses. Ulcers

tend to develop in depigmented skin about the region of

maximum tension in contractures (figure 6). We also

recommend all non healing ulcers (up to 12 weeks) should



be excised with a margin of healthy tissue and examined

microscopically.

Conclusion

Marjolin’s ulcers are aggressive tumours occurring in scars.

Its menace appears to be worse in Nigeria. Health education

is needed to discourage patients with cutaneous ulcers from

presenting to traditional healers and chemists. Education is

needed as well to prevent late presentation. Early adequate

treatment of all ulcers and scars will certainly reduce the

incidence of Marjolin’s ulcer. This includes early excision of

full thickness burn injury and skin cover; excision of scars,

and flap cover of released contractures across mobile joints.

Aggressive treatment and close follow-up are urgently

needed to improve outcomes in our environment.

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LIST OF FIGURES



Documents

Review of Marjolin Ulcer