review of marjolin ulcer
TRANSCRIPT
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
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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
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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
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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
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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
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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.
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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.
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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
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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
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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
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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
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