Review Article
Malignant Transformation in Chronic Osteomyelitis: Recognition and Principles of Management Abstract Michalis Panteli, MD, MRCS Ravindra Puttaswamaiah, MBBS, MS David W. Lowenberg, MD Peter V. Giannoudis, MB, MD, FRCS
From the Academic Department of Trauma and Orthopaedic Surgery, Leeds Teaching Hospitals, University of Leeds, West Yorkshire, UK (Dr. Panteli), the Department of Orthopaedic Surgery, SPARSH Hospital for Advanced Surgeries, Bangalore, India (Dr. Puttaswamaiah), the Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA (Dr. Lowenberg), and the Academic Department of Trauma and Orthopaedic Surgery, Leeds Teaching Hospitals, University of Leeds, NIHR Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, West Yorkshire, UK (Dr. Giannoudis). J Am Acad Orthop Surg 2014;22: 586-594 http://dx.doi.org/10.5435/ JAAOS-22-09-586 Copyright 2014 by the American Academy of Orthopaedic Surgeons.
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Malignant transformation as a result of chronic osteomyelitis represents a relatively rare and late complication with a declining incidence in the modern world. For most patients, the interval between the occurrence of the original bacterial infection and the transformation to malignant degeneration is several years. The diagnosis of malignant transformation in a chronic discharging sinus requires a high index of clinical suspicion. Wound biopsies should be obtained early, especially with the onset of new clinical signs such as increased pain, a foul smell, and changes in wound drainage. Squamous cell carcinoma is the most common presenting malignancy. Definitive treatment is amputation proximal to the tumor or wide local excision, combined with adjuvant chemotherapy and radiation therapy in selected patients. Early diagnosis may sometimes allow for treatment consisting of en bloc excision and limb salvage techniques. However, the most effective treatment is prevention with definitive treatment of the osteomyelitis, including adequate débridement, wide excision of the affected area, and early reconstruction.
A
cute inflammatory response and wound healing is a wellorchestrated physiologic process that involves a complex series of biologic events.1,2 Following high-energy trauma, development of infection may result from compromised soft tissue and poor bone vascularity, systemic compromise of the host, and virulent or resistant organisms. All of these factors impair healing3 and may potentially lead to a chronic, refractory condition.4 Chronic osteomyelitis represents an inflammatory process accompanied by bone destruction5 caused by complex microbial colonies enclosed in a polysaccharide/protein matrix that these colonies produce.6 This
biofilm protects the bacteria from the host’s immune system and from the systemic effect of antibiotics, resulting in difficulty in eradicating an established infection.6 The reasons for difficulties encountered during eradication are multifactorial, relating not only to the relative impermeability of the biofilm to antibiotic influx, but also to a change in the state of the bacterial cells themselves. During the initial infectious phase, the bacteria are in a planktonic phase with a high metabolic rate and generational rate. This makes the bacteria sensitive to the most commonly used antibiotics. However, once the biofilm has matured, these bacteria convert to a semidormant, sessile state.
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This lowered metabolic rate reduces their susceptibility to the same antibiotics, often by a factor of 103. This action, combined with the fact that the bacteria are able to physically hide in the organized biofilm sludge, makes them even further immune to the effects of systemic antibiotic therapy. The Cierny-Mader classification is the first system to incorporate prognostic factors according to the anatomic type and physiologic class of the host, delineating treatment of each clinical stage of the osteomyelitis.7 Although the antibiotic choice, delivery type, and duration of treatment remain controversial,8 it is generally accepted that adequacy of débridement with wide excision remains the most important clinical predictor of a successful outcome.6 Most experts in the treatment of chronic osteomyelitis of long bones agree that it is a surgical disease with positive outcomes achieved only with complete débridement of all infected bone and soft tissue, as well as proper dead space management, followed by later reconstruction. Parasitic infections and their effect on stem cell signaling represent one of the oldest theories in the origin of cancer,9,10 with up to 25% of malignancies being attributed to chronic inflammation and infectious agents.10,11 In studies of patients with chronic osteomyelitis, there is highlevel evidence that infection acts as a promoting agent in the complex process of carcinogenesis.9,10 Prompt diagnosis and aggressive management of the malignant transformations that arise from sites of
chronic osteomyelitis are critical to the prognosis and final outcome. The cornerstones of management include amputation proximal to the defect in patients with advanced nonsalvageable disease or wide surgical excision in selected patients, followed by soft-tissue and bone reconstruction.
Epidemiology Osteomyelitis is an ancient disease; there is evidence of its existence in ancient creatures more than 250 million years ago.12 Hippocrates was the first to describe cases of osteomyelitis in humans.12 With the introduction of antibiotics in the 1940s, there was a dramatic drop in mortality from osteomyelitis; at that time, it became a potentially curable disease.12 However, it remains a challenging problem, especially in patients with open and complex fractures. Currently, the incidence of hematogenous osteomyelitis seems to be declining and has been reported to have decreased from an annual incidence of 87 cases per 10,000 to 42 cases per 10,000 over recent decades.13 In contrast to hematogenous osteomyelitis, the incidence of osteomyelitis after a contiguous focus of infection (ie, following trauma, surgery, or implants) is increasing.5 Trauma remains the most common cause of osteomyelitis.14 Infection rates in open long bone fractures range from 4% to 64%, whereas recurrence rates following bony infection range between 20% to 30%.13
Marjolin ulcer refers to a malignant degeneration arising from areas of chronic inflammation or injury of the skin, regardless of the origin of the lesion or the type of malignancy.11 An estimated 1.7% of chronic wounds undergo malignant degeneration,15 whereas Marjolin ulcers have been reported to occur in 1.6% to 23% of all patients with chronic osteomyelitis.16-18 Developing countries with limited access to medical treatment have a higher incidence of Marjolin ulcers and disease state because of the frequently delayed presentation.17,18 Marjolin ulcer most often occurs in men aged 18 to 40 years10,14,16 (Table 1). The malignant transformation takes place over the course of several years, with a latent period of 27 to 30 years,16,17,19,20 ranging from 18 to 72 years (time of presentation of osteomyelitis to malignant transformation).16,19 Acute cases have also been reported but are rare.21,22 The duration of chronic osteomyelitis represents the most important factor for malignant transformation.16 The tibia is the most frequently affected long bone,10,14,16 followed by the femur14,16 and the foot;14,16 in contrast, the bones of the upper extremity are rarely affected.14,20 In paraplegic patients, pressure sores and associated osteomyelitis are resistant to intervention and generally contribute to a steady decline in the patient’s condition.21 Radical treatment and reconstruction of the defect can be challenging and may be associated with a high mortality rate.21,22 Marjolin ulcer represents a welldescribed complication, especially in
Dr. Lowenberg or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Stryker; serves as a paid consultant to Stryker and Ellipse Technologies; and serves as a board member, owner, officer, and committee member of the Foundation for Orthopaedic Trauma. Dr. Giannoudis or an immediate family member has received royalties from Biomet; is a member of a speakers’ bureau or has made paid presentations on behalf of Synthes, Medtronic Sofamor Danek, and Olympus Biotech; serves as a paid consultant to Synthes and Olympus Biotech; serves as an unpaid consultant to Amgen; has received research or institutional support from DePuy, Synthes, and Pfizer; and serves as a board member, owner, officer, or committee member of the Orthopaedic Trauma Association, the British Trauma Society, the British Orthopaedic Association, the European Federation of National Associations of Orthopedics and Traumatology, and the Orthopaedic Trauma Association. Neither of the following authors nor any immediate family member has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Panteli and Dr. Puttaswamaiah.
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Malignant Transformation in Chronic Osteomyelitis: Recognition and Principles of Management
Table 1 Demographics and Type of Malignancya Study
No. Pts (Sex)
Age (yr)
Hwang et al23 Fairbairn and Hamilton21
1, M 1, M
79 25
Alami et al20
6, M 1, F
Lack and McKinley22
1, F
54.5 6 10.2 (38 to 71) 66
Kersh et al24 Hall et al25 Wolf et al26 Rauh et al27 Pandey et al28
1, M 1, M 1, M 1, M 1, M
62 54 60 69 65
Pandey et al28
1, M
24
Ogawa et al19 Zlowodzki et al29
1, M 1, M
60 51
Smidt et al30 Altay et al16
1, M 7, M
Puri et al31 Campodonico and Carmignani32
1, M 1, M
Site
Time Since Initial Injury (yr)
Proximal third of anterior tibia Ischial tuberosities, sacrum and femoral head, complicated with multiple pressure sores Tibia: 4 pts femur: 2 pts humerus: 1 pts Ischium
15 10 24.5 6 11.0 (9 to 40) 10 to 12
Fifth toe Greater trochanter Anterior side of proximal tibia Thumb-distal phalanx Medial side of distal third of the leg Anteromedial aspect of the upper leg Elbow Distal femur
1 14 58 10 34
50 59.5 6 3.2 (54 to 63)
Leg Ankle: 2; calcaneus: 2; forefoot: 3
40 26.9 6 14.8 (4 to 50)
40 23
Mid third of anterior tibia Hip and pelvis
21 10 15
5 1.3 (continued)
MRSA = methicillin-resistant Staphylococcus aureus, SCC = squamous cell carcinoma a Following a review of the literature, we identified 15 eligible studies (case series reporting on a total of 28 patients).16,19-32 Studies selected were original articles that fulfilled the following inclusion criteria: (1) studies enrolled adult patients with evidence of malignant transformation of chronic osteomyelitis wound (ie, Marjolin ulcer); (2) studies were published within the last 10 years; (3) adequate information was included; (4) articles were published in the English language; and (5) the full text of each article was available.
developed areas of the world in which the longevity of this patient population is extended.21,22 Marjolin ulcers predominately involve aggressive squamous cell carcinomas (SCC).10,16,19,23,29,33 Other types of malignancies associated with chronic osteomyelitis include basal cell carcinoma,10,19 fibrosarcoma,10,16,19 myeloma,10,16,19,29 10,16,19,29 angiosarcoma, rhabdomyosarcoma,10,16,19,29 fibroblastic osteosarcoma,31 adenocarcinoma,29 B cell lymphoma,16,19,29 plasmacytoma,16 malignant fibrous histiocytoma,16,29 malignant hemangioendothelioma,29 reticulosarcoma,19 and fibroblastic osteosarcoma.19,29,34
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Etiopathogenesis The exact mechanism of malignant transformation of Marjolin ulcer remains unclear and is controversial.33 The main hypothesized theory is that chronic inflammation is carcinogenic.10,15,17,20,21,33,35-37 In general, chronic inflammation favors carcinogenesis, malignant transformation, tumor growth, invasion, and metastatic spread.11,35-37 Chronic inflammatory mediators also exert pleiotropic effects on the development of cancer,11 while inflammatory cytokines may potentially lead to an altered expression of tumor suppres-
sion genes, such as tumor protein p53.9,15 Other hypothesized carcinogenic settings include (1) the lymphatic obliteration that decreases the antigen presentation to the host;17,33 (2) toxins released from the damaged tissues that are speculated to cause cellular mutations;15,21,33 (3) an immunologic etiology in which the inflamed tissues may become depleted of immunologic cells so that tumors can escape immunodetection;15,17,21,33 (4) implantation of traumatic epithelial elements that may cause a foreign-body response;15,33 (5) heredity;21,33 (6) co-carcinogen theory speculating that the original insult is not in itself carcinogenic but may activate preexisting
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Table 1 (continued ) Demographics and Type of Malignancya Tumor Size (cm)
Histologic Type
4· 7 Multi-focal tumor
SCC Moderately differentiated SCC with a highly infiltrative growth pattern and evidence of perineural and perivascular invasion Well-differentiated SCC with bone invasion: 5 cases; invasive SCC: 2 cases Well-differentiated SCC with bone invasion
Not mentioned Not mentioned
Pseudomonas aeruginosa Not mentioned Pseudomonas aeruginosa
8· 5
SCC SCC Moderately differentiated SCC, large keratinizing type Malignant fibrous histiocytoma of bone grade 4 SCC SCC (deceased pt; poorly differentiated, invasive squamous epithelial cells) High-grade fibroblastic osteosarcoma
Staphylococcus aureus Not mentioned Staphylococcus most common; most pts had mixed infections Not mentioned
Not mentioned
Undifferentiated sarcoma
Not mentioned
Not mentioned 14 1.3 · 1 · 0.3 Not mentioned 6· 2 Entire length of distal phalanx 20 · 15 20 · 7 14 · 18 Not mentioned Not mentioned Not mentioned
Pathogen Isolated
Not mentioned
Serratia marasacens and Prevotella; then MRSA and Pseudomonas Well to moderately differentiated invasive SCC Not mentioned Moderately differentiated SCC with invasion Not mentioned into skin layers Epithelioma cuniculatum (variant of SCC) b-hemolytic Streptococcus and Corynebacterius spp. Moderately differentiated SCC Pseudomonas aeruginosa; Staphylococcus aureus
MRSA = methicillin-resistant Staphylococcus aureus, SCC = squamous cell carcinoma a Following a review of the literature, we identified 15 eligible studies (case series reporting on a total of 28 patients).16,19-32 Studies selected were original articles that fulfilled the following inclusion criteria: (1) studies enrolled adult patients with evidence of malignant transformation of chronic osteomyelitis wound (ie, Marjolin ulcer); (2) studies were published within the last 10 years; (3) adequate information was included; (4) articles were published in the English language; and (5) the full text of each article was available.
neoplastic cells or make them more susceptible to other carcinogenic factors;21,33 and (7) ultraviolet rays.33 Most likely, the process of malignant transformation represents a multifactorial event having several contributing factors.21 Another factor that has been reported to contribute to the development of carcinogenesis in the host is the pan-genome or supragenome found in most accepted bacterial infections. According to the Distributed Genome Hypothesis38 that addresses chronic polymicrobial infections, the occurrence of real-time horizontal gene transfer further poses confusion to the host immune system, requiring September 2014, Vol 22, No 9
it to adapt at an inordinate rate, thus resulting in latent mutations.39,40
symptoms include hyperkalemia, weight loss associated with a reduced oral intake,25 and hyperpigmented surrounding skin.28
Clinical Features Increased pain,14,16,19-21,26-29,30,32 a foul smell,16,19,20,24,26-28,32 and increased drainage19-21,24,28,29,31 are the most common presenting symptoms of Marjolin ulcers. Other common characteristics include an enlarging or exophytic mass,14,16,19,21,24,26,31 erythema,24,29 bleeding,26,32 continued unresponsiveness to therapy,19,31,39 lymphadenopathy,16,19 and hemorrhage.19 Other, less frequently presenting
Imaging Features The malignant transformation starts from the skin or the epithelial lining of the fistula,20 and if neglected, infiltrates the bone in a permeative fashion.26 Several imaging modalities are used to detect each stage of the disease, thus aiding in the diagnosis. Periosteal changes19 and progressive bone destruction are evident on plain radiographs,19,28 with
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Malignant Transformation in Chronic Osteomyelitis: Recognition and Principles of Management
Figure 1
Figure 2
Clinical photograph demonstrating ulceration in chronic osteomyelitis.
AP (A) and lateral (B) radiographs demonstrating changes associated with chronic osteomyelitis (periosteal thickening, focal bony lysis, endosteal scalloping, loss of bony trabecular architecture, new bone apposition, peripheral sclerosis).
osteolysis seen in the more advanced stages of the disease.20,24,26,27,31 Following invasion of the bone marrow, it can becomes sclerotic26 or, conversely, medullary destruction may be evident.25 Other common characteristics seen on radiographic images include a soft-tissue mass19,25 and soft-tissue swelling.24 Serial radiographs of the affected area are useful in detecting the subtle changes that suggest malignant transformation,31 although they cannot always confirm or refute the malignancy. CT best visualizes the extent of bone involvement, and staging CT is particularly useful to detect distant metastases.19,26 MRI can assess soft-tissue involvement. Soft-tissue masses19,27 and bone marrow edema26 are the most common presentations seen on MRI; however, these changes are also seen in chronic osteomyelitis.19,27 MRI
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is also used to differentiate SCC from other types of soft-tissue neoplasms.24 It has also been reported that MRI is the modality that best correlates with the histologic findings.26 Nevertheless, there are cases in which no sign of malignancy is evident on any of the imaging modalities. As stated, osteolysis might be the only sign, especially at the initial stages of the disease; however, it is also commonly seen in an otherwise uncomplicated case of chronic osteomyelitis.28 Therefore, a high clinical suspicion is paramount in the early detection of malignant transformation.
Diagnostic Approach Diagnosis can be very challenging because only subtle changes may occur in the sequence of events in
chronic osteomyelitis (Figure 1). The combination of obtaining a detailed history and conducting a comprehensive clinical examination17 provides the physician with valuable information. In principle, patients with chronic osteomyelitis ulcers/ fistulas (Figure 2) require a close follow-up;26 any chronic wound that demonstrates characteristic changes should raise the suspicion of malignant transformation.19 Zlowodzki et al29 suggest that frozen sections and permanent pathology sections should be obtained during the initial débridement of all chronic infectious or tumorous conditions to help ensure that there is no underlying malignancy. Confirmation of a malignancy may be best achieved by obtaining biopsies at multiple sites and depths to increase the diagnostic accuracy,19 thus reducing the risk of obtaining false-negative results.28 Samples should include tissue from the sinus tract, the ulcer, and the bone.16 Some physicians advocate that biopsies should also be obtained at regular intervals during the healing
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process of every wound associated with chronic osteomyelitis, continuing until the wound is completely healed.21 The best time for obtaining a biopsy remains controversial, but most physicians recommend 3 to 4 months after initiation of treatment and when the wound has not responded to standard treatment.15 Others suggest that because of the small incidence of malignant degeneration of chronic wounds, only suspicious lesions should be biopsied.15 Once a malignancy is diagnosed, distant metastases can be ruled out with the use of staging CT, MRI, and PET.19,23,26 CT-guided biopsies may be of use in cases involving metastatic disease.25 Lymph node biopsies may also be required to show evidence of lymphatic disease;21 this is the most common site of metastasis,27 whereas a biopsy of the sentinel lymph node may be particularly useful in clinically nodenegative patients.21 Nevertheless, the presence of satellite nodes can often indicate an inflammatory reaction.20
osteomyelitis is poor, mainly because of the lack of awareness and, therefore, late diagnosis.21 When the condition is diagnosed early, the outcome following complete excision is more favorable.10 Generally, these malignancies are aggressive and have a tendency of local recurrence and lymph node metastases,10 especially with highgrade lesions.16 In patients with SCC, lymph node metastasis has been observed in 10% to 20% of patients,16 while others report rates of .40%.27 The overall prognosis is determined by the rate of lymph node metastasis and distant metastasis,16,26 with most of the metastases presenting within the first 18 months.27 Patients with no metastatic disease during the first 3 years usually have a good prognosis.27 The presence of lymphatic spread or distant metastasis reduces the survival rate to 35% to 50%,20 whereas the overall mortality has been reported to be as high as 9.6%.14
Management Differential Diagnosis The features of osteomyelitis (ie, lytic lesions, cortical destruction) may resemble common features reported in several other conditions, thus making it even more challenging to distinguish between these conditions. Further evaluation and histopathologic examination is of paramount importance to allow for early identification and appropriate treatment. Other skin conditions involved in the differential diagnosis of SCC include basal cell carcinoma, Bowen disease, cutaneous granulomas, psoriasis, eczema, and keratoacanthomas.24
Prognosis The prognosis of malignant transformation that results from chronic September 2014, Vol 22, No 9
The definitive treatment of choice as suggested by most clinicians has been amputation proximal to the tumor16,20,24,28 (Table 2). Although this is an aggressive action, amputation offers a relatively simple solution for eradicating both the chronic osteomyelitis and the malignancy. Moreover, it provides a faster and safer recovery in advanced complex cases.20 Recently, wide complete local excision has also been proposed in selected patients and before any distant metastasis is evident.15,19,23 When the histologic type of a Marjolin ulcer is SCC, it has been suggested that the resection margin should be at least 2 cm, along with a clear deep margin.23 The use of Mohs micrographic surgery has also been reported in the absence of distant metastases and lymph node involve-
ment.15 With this technique, the tumor is followed microscopically through serial sections, thus ensuring complete eradication.15 Following wide resection, free-tissue transfer may be used to cover the soft-tissue defect, whereas free vascularized osseous transfer or bone transport via distraction osteogenesis can be used to restore the segmental bone defect.23 When surgical excision of the lesion is not possible, amputation should be considered.17 In the presence of paraplegia and associated chronic pressure sores in the sacral and ischial regions, radical surgical management with hemipelvectomy and extensive flap reconstruction has been proposed.21,22 Because of the late diagnosis and hence poor prognosis, the need for interventions necessary to prevent the malignant transformation is stressed.21,22 Additionally, the patient should be screened for lymphadenopathy and distant metastases. However, it remains controversial whether regional lymphadenectomy is required16 because lymph node enlargement is often the result of inflammatory causes and subsides following treatment.16 However, if lymph node enlargement persists for 6 to 12 weeks after amputation, surgical treatment is warranted.15,16 Adjuvant chemotherapy25 and/or radiation therapy19,25,28 may be useful in the presence of inoperative metastatic disease21,27 and highgrade tumors.31 Finally, the patient should be seen for regular follow-up to examine for any signs of local recurrence, palpable regional lymph nodes, or evidence of distant metastases.23
Summary Malignant transformation as a result of chronic osteomyelitis represents
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Malignant Transformation in Chronic Osteomyelitis: Recognition and Principles of Management
Table 2 Staging, Treatment, and Outcome Study
Metastases (Gradinga)
Lymph Node Status
Hwang et al23
None affected
None (N0M0)
Fairbairn and Hamilton21
None affected
None (N0M0)
None affected One lymph node positive to SCC metastasis 1 residual bilateral pelvic and inguinal lymphadenopathy on staging CT None affected None affected None affected
None (All patients N0M0) Lungs 1 extensive metastatic abdominal disease (N1M1)
Alami et al20 Lack and McKinley22
Kersh et al24 Hall et al25 Wolf et al26
Ogawa et al19
Second operation: 1 of 29 lymph nodes was positive to SCC 1 single axillary mass 7 · 8 cm (inflammation without malignancy) None affected Inguinal lymphadenopathy; biopsies showed it was reactive None affected
Zlowodzki et al29 Smidt et al30 Altay et al16
One lymph node was positive to malignant fibrous histiocytoma Only reactive response 4 patients (including deceased pt)
Rauh et al27 Pandey et al28 Pandey et al28
Puri et al31 Campodonico and Carmignani32
2-3 palpable inguinal nodes (1 · 1 cm), but were not considered to be significant Spread to pelvic lymph nodes
None (N0M0) Both lungs (N0M1) None (N0M0)
Tip of the small finger 1 flexor tendon sheath 1 lungs (N1M1) None (N0M0) None (N0M0) None (N0M0)
None (N1M0) None (N0M0) In 1 pt, deceased (N0M0, 3 pts; N1M0, 2 pts; N1M1, 1 pt) None (N0M0) None (N1M0) (continued)
a
NM staging of soft-tissue sarcomas: N (describes lymph nodes metastasis): N0 = sarcoma has not spread to neighboring nodes, N1 = sarcoma has spread to neighboring nodes. M (describes distant metastasis): M0 = sarcoma has not metastasized, M1 = sarcoma has metastasized to distant organs and/or tissues MCPJ = metacarpophalangeal joint, MTPJ = metatarsophalangeal joint, SCC = squamous cell carcinoma
a relatively rare and late complication. Its incidence appears to be declining in countries with more modern health care, but it remains a problem in developing countries. The interval between the original bacterial infection and malignant degeneration is, in
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most cases, many years and often can be decades. Clinical suspicion should be high in every case of chronic discharging osteomyelitis, combined with a low threshold of obtaining wound biopsies, especially with the onset of new clinical signs. The most
effective prevention is the definitive treatment of the osteomyelitis, with adequate débridement and wide excision of the affected area and early reconstruction with the use of modern limb salvage and reconstruction methods.
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Table 2 (continued ) Staging, Treatment, and Outcome Type of Treatment
Recurrence (Pts Deceased)
Follow-up (mos)
Latissimus dorsi free flap 1 free vascularized fibula (from contralateral side) Abdomino-perineal resection and colostomy; radical excision of sacral and ischial pressure sore SCC; débridement of osteomyelitic left hemipelvis; disarticulation and excision of femoral head, femur, tibia, and fibula; and complete lower limb myocutaneous fillet flap reconstruction, pedicled on the femoral vessels Amputation in 6 pts; 1 pt refused amputation Hemipelvectomy Fifth toe amputation through MTPJ, followed by wide resection of the affected skin Not mentioned
18
No (No)
Not mentioned
Not mentioned (No)
60 3 16
No (No) Extensive metastatic disease (Yes) No (No)
Not mentioned
Not mentioned (Not mentioned) No (No) 1 yr later and again 4 mos after first recurrence (Yes)
Knee exarticulation 10 Initially amputation through the distal portion of the proximal 22 phalanx; then wide of the proximal phalanx down to the MCPJ. First relapse: Wide resection of the mass including thumb and index finger ray amputations 1 radical axillary dissection 1 radiation therapy. Second relapse: Radiation therapy 1 palliative small finger ray amputation. Below-knee amputation 24
No (No)
Below-knee amputation Amputation at the midshaft of the humerus (1) Irrigation and débridement of the draining sinus (before histology); (2) elective reconstructive surgery; (3) irrigation and débridement of the femur with resection of the distal femur approximately 15 cm above the knee for staged reconstruction 1 cement spacer; or (4) hip disarticulation 1 chemotherapy. Supracondylar leg amputation Below-knee amputation: 4 pts; Syme amputation: 2 pts; wide resection: 1 patient. Lymphadenectomy: 4 pts. The patient with distant metastasis also had radiation therapy.
Not mentioned 5 27
No (No) No (No) No (No)
12 68 6 42 (22 to 147)
No (No) 1 pt: local recurrence 19 mos after primary amputation; required a more proximal amputation (died)
Below-knee amputation
Not mentioned
Not mentioned (Not mentioned)
Wide excision
3
Pt deceased 3 mos postop (Yes)
a
NM staging of soft-tissue sarcomas: N (describes lymph nodes metastasis): N0 = sarcoma has not spread to neighboring nodes, N1 = sarcoma has spread to neighboring nodes. M (describes distant metastasis): M0 = sarcoma has not metastasized, M1 = sarcoma has metastasized to distant organs and/or tissues MCPJ = metacarpophalangeal joint, MTPJ = metatarsophalangeal joint, SCC = squamous cell carcinoma
References: Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 8 is a level I study. References 2, 10, 11, 14, 16-34, and 36 are level IV studies. September 2014, Vol 22, No 9
References 1, 3-7, 9, 12, 13, 15, 35, 37-39, and 40 are level V studies.
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Malignant Transformation in Chronic Osteomyelitis: Recognition and Principles of Management concepts. J Am Acad Orthop Surg 2005;13 (6):417-427. 4. Cierny G III, DiPasquale D: Treatment of chronic infection. J Am Acad Orthop Surg 2006;14(10 Spec No.):S105-S110. 5. Lew DP, Waldvogel FA: Osteomyelitis. Lancet 2004;364(9431):369-379. 6. Forsberg JA, Potter BK, Cierny G III, Webb L: Diagnosis and management of chronic infection. J Am Acad Orthop Surg 2011;19(suppl 1):S8-S19. 7. Cierny G III, Mader JT, Penninck JJ: A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res 2003;414:7-24. 8. Conterno LO, da Silva Filho CR: Antibiotics for treating chronic osteomyelitis in adults. Cochrane Database Syst Rev 2009;3:CD004439. 9. Sell S: Infection, stem cells and cancer signals. Curr Pharm Biotechnol 2011;12 (2):182-188. 10. Samaras V, Rafailidis PI, Mourtzoukou EG, Peppas G, Falagas ME: Chronic bacterial and parasitic infections and cancer: A review. J Infect Dev Ctries 2010;4(5):267-281. 11. Multhoff G, Molls M, Radons J: Chronic inflammation in cancer development. Front Immunol 2011;2:98. 12. Klenerman L: A history of osteomyelitis from the Journal of Bone and Joint Surgery: 1948 TO 2006. J Bone Joint Surg Br 2007; 89(5):667-670. 13. Lazzarini L, Mader JT, Calhoun JH: Osteomyelitis in long bones. J Bone Joint Surg Am 2004;86(10):2305-2318. 14. McGrory JE, Pritchard DJ, Unni KK, Ilstrup D, Rowland CM: Malignant lesions arising in chronic osteomyelitis. Clin Orthop Relat Res 1999;362:181-189. 15. Trent JT, Kirsner RS: Wounds and malignancy. Adv Skin Wound Care 2003; 16(1):31-34. 16. Altay M, Arikan M, Yildiz Y, Saglik Y: Squamous cell carcinoma arising in chronic osteomyelitis in foot and ankle. Foot Ankle Int 2004;25(11):805-809. 17. Kerr-Valentic MA, Samimi K, Rohlen BH, Agarwal JP, Rockwell WB: Marjolin’s ulcer: Modern analysis of an ancient problem. Plast Reconstr Surg 2009;123(1): 184-191.
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18. Onah II, Olaitan PB, Ogbonnaya IS, Onuigbo WI: Marjolin’s ulcer (correction of ucler) at a Nigerian hospital (19932003). J Plast Reconstr Aesthet Surg 2006; 59(5):565-566. 19. Ogawa B, Chen M, Margolis J, Schiller FJ, Schnall SB: Marjolin’s ulcer arising at the elbow: A case report and literature review. Hand (N Y) 2006;1(2):89-93. 20. Alami M, Mahfoud M, El Bardouni A, Berrada MS, El Yaacoubi M: Squamous cell carcinoma arising from chronic osteomyelitis. Acta Orthop Traumatol Turc 2011;45(3):144-148. 21. Fairbairn NG, Hamilton SA: Management of Marjolin’s ulcer in a chronic pressure sore secondary to paraplegia: A radical surgical solution. Int Wound J 2011;8(5): 533-536. 22. Lack W, McKinley T: Marjolin’s ulcer: Incidental diagnosis of squamous cell carcinoma on hemipelvectomy for recalcitrant pelvic osteomyelitis. Iowa Orthop J 2010;30:174-176. 23. Hwang KT, Youn S, Kim JT, Lee SH, Ng SW, Kim YH: Use of latissimus dorsi flap pedicle as a T-junction to facilitate simultaneous free fibular flap inset in lower extremity salvage. J Plast Reconstr Aesthet Surg 2012;65(4):517-520. 24. Kersh S, Lakhani S, Ramanujam CL, Derk F, Zgonis T: Concomitant acute osteomyelitis and squamous cell carcinoma of the foot: A case report. Clin Podiatr Med Surg 2010;27(4):635-641. 25. Hall AB, Buehler KE, Philipneri M: Hypercalcemia complicating Marjolin’s ulcer. Mil Med 2009;174(3):308-310. 26. Wolf H, Platzer P, Vécsei V: Verrucous carcinoma of the tibia arising after chronic osteomyelitis: A case report. Wien Klin Wochenschr 2009;121(1-2):53-56. 27. Rauh MA, Duquin TR, McGrath BE, Mindell ER: Spread of squamous cell carcinoma from the thumb to the small finger via the flexor tendon sheaths. J Hand Surg Am 2009;34(9):1709-1713. 28. Pandey M, Kumar P, Khanna AK: Marjolin’s ulcer associated with chronic osteomyelitis. J Wound Care 2009;18(12):504-506. 29. Zlowodzki M, Allen B, Schreibman KL, Vance RB, Kregor PJ: Malignant fibrous histiocytoma of bone arising in chronic
osteomyelitis. Clin Orthop Relat Res 2005; 439(439):269-273. 30. Smidt LS, Smidt LF, Chedid MB, Bavaresco CS, Chedid MF: Radical surgical treatment for Marjolin ulcer occurring after chronic osteomyelitis. South Med J 2005;98 (10):1053. 31. Puri A, Parasnis AS, Udupa KV, Duggal A, Agarwal MG: Fibroblastic osteosarcoma arising in chronic osteomyelitis. Clin Radiol 2003;58(2):170-172. 32. Campodonico F, Carmignani G: Pelvic sarcoma arising from chronic osteomyelitis. J Clin Pathol 2003;56(7):558-559. 33.
Chalya PL, Mabula JB, Rambau P, et al: Marjolin’s ulcers at a university teaching hospital in Northwestern Tanzania: A retrospective review of 56 cases. World J Surg Oncol 2012;10:38.
34. Smith J, Mello LF, Nogueira Neto NC, et al: Malignancy in chronic ulcers and scars of the leg (Marjolin’s ulcer): A study of 21 patients. Skeletal Radiol 2001;30(6): 331-337. 35. Kenny PA, Nelson CM, Bissell MJ: The ecology of tumors: By perturbing the microenvironment, wounds and infection may be key to tumor development. Scientist 2006;20(4):30. 36. Bissell MJ, Kenny PA, Radisky DC: Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: The role of extracellular matrix and its degrading enzymes. Cold Spring Harb Symp Quant Biol 2005;70:343-356. 37. Coussens LM, Werb Z: Inflammation and cancer. Nature 2002;420(6917):860-867. 38. Ehrlich GD: The biofilm and distributed genome paradigms provide a new theoretical structure for understanding chronic bacterial infections. Presented at the 41st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, Illinois, December 16-19, 2001. 39. Ehrlich G, Hu F, Post J: Role for biofilms in infectious disease. Washington, DC, ASM Press, 2004. 40. Ehrlich GD, Hu FZ, Shen K, Stoodley P, Post JC: Bacterial plurality as a general mechanism driving persistence in chronic infections. Clin Orthop Relat Res 2005; 437:20-24.
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Malignant Transformation in Chronic Osteomyelitis: Recognition and Principles of Management Abstract Michalis Panteli, MD, MRCS Ravindra Puttaswamaiah, MBBS, MS David W. Lowenberg, MD Peter V. Giannoudis, MB, MD, FRCS
From the Academic Department of Trauma and Orthopaedic Surgery, Leeds Teaching Hospitals, University of Leeds, West Yorkshire, UK (Dr. Panteli), the Department of Orthopaedic Surgery, SPARSH Hospital for Advanced Surgeries, Bangalore, India (Dr. Puttaswamaiah), the Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA (Dr. Lowenberg), and the Academic Department of Trauma and Orthopaedic Surgery, Leeds Teaching Hospitals, University of Leeds, NIHR Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, West Yorkshire, UK (Dr. Giannoudis). J Am Acad Orthop Surg 2014;22: 586-594 http://dx.doi.org/10.5435/ JAAOS-22-09-586 Copyright 2014 by the American Academy of Orthopaedic Surgeons.
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Malignant transformation as a result of chronic osteomyelitis represents a relatively rare and late complication with a declining incidence in the modern world. For most patients, the interval between the occurrence of the original bacterial infection and the transformation to malignant degeneration is several years. The diagnosis of malignant transformation in a chronic discharging sinus requires a high index of clinical suspicion. Wound biopsies should be obtained early, especially with the onset of new clinical signs such as increased pain, a foul smell, and changes in wound drainage. Squamous cell carcinoma is the most common presenting malignancy. Definitive treatment is amputation proximal to the tumor or wide local excision, combined with adjuvant chemotherapy and radiation therapy in selected patients. Early diagnosis may sometimes allow for treatment consisting of en bloc excision and limb salvage techniques. However, the most effective treatment is prevention with definitive treatment of the osteomyelitis, including adequate débridement, wide excision of the affected area, and early reconstruction.
A
cute inflammatory response and wound healing is a wellorchestrated physiologic process that involves a complex series of biologic events.1,2 Following high-energy trauma, development of infection may result from compromised soft tissue and poor bone vascularity, systemic compromise of the host, and virulent or resistant organisms. All of these factors impair healing3 and may potentially lead to a chronic, refractory condition.4 Chronic osteomyelitis represents an inflammatory process accompanied by bone destruction5 caused by complex microbial colonies enclosed in a polysaccharide/protein matrix that these colonies produce.6 This
biofilm protects the bacteria from the host’s immune system and from the systemic effect of antibiotics, resulting in difficulty in eradicating an established infection.6 The reasons for difficulties encountered during eradication are multifactorial, relating not only to the relative impermeability of the biofilm to antibiotic influx, but also to a change in the state of the bacterial cells themselves. During the initial infectious phase, the bacteria are in a planktonic phase with a high metabolic rate and generational rate. This makes the bacteria sensitive to the most commonly used antibiotics. However, once the biofilm has matured, these bacteria convert to a semidormant, sessile state.
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This lowered metabolic rate reduces their susceptibility to the same antibiotics, often by a factor of 103. This action, combined with the fact that the bacteria are able to physically hide in the organized biofilm sludge, makes them even further immune to the effects of systemic antibiotic therapy. The Cierny-Mader classification is the first system to incorporate prognostic factors according to the anatomic type and physiologic class of the host, delineating treatment of each clinical stage of the osteomyelitis.7 Although the antibiotic choice, delivery type, and duration of treatment remain controversial,8 it is generally accepted that adequacy of débridement with wide excision remains the most important clinical predictor of a successful outcome.6 Most experts in the treatment of chronic osteomyelitis of long bones agree that it is a surgical disease with positive outcomes achieved only with complete débridement of all infected bone and soft tissue, as well as proper dead space management, followed by later reconstruction. Parasitic infections and their effect on stem cell signaling represent one of the oldest theories in the origin of cancer,9,10 with up to 25% of malignancies being attributed to chronic inflammation and infectious agents.10,11 In studies of patients with chronic osteomyelitis, there is highlevel evidence that infection acts as a promoting agent in the complex process of carcinogenesis.9,10 Prompt diagnosis and aggressive management of the malignant transformations that arise from sites of
chronic osteomyelitis are critical to the prognosis and final outcome. The cornerstones of management include amputation proximal to the defect in patients with advanced nonsalvageable disease or wide surgical excision in selected patients, followed by soft-tissue and bone reconstruction.
Epidemiology Osteomyelitis is an ancient disease; there is evidence of its existence in ancient creatures more than 250 million years ago.12 Hippocrates was the first to describe cases of osteomyelitis in humans.12 With the introduction of antibiotics in the 1940s, there was a dramatic drop in mortality from osteomyelitis; at that time, it became a potentially curable disease.12 However, it remains a challenging problem, especially in patients with open and complex fractures. Currently, the incidence of hematogenous osteomyelitis seems to be declining and has been reported to have decreased from an annual incidence of 87 cases per 10,000 to 42 cases per 10,000 over recent decades.13 In contrast to hematogenous osteomyelitis, the incidence of osteomyelitis after a contiguous focus of infection (ie, following trauma, surgery, or implants) is increasing.5 Trauma remains the most common cause of osteomyelitis.14 Infection rates in open long bone fractures range from 4% to 64%, whereas recurrence rates following bony infection range between 20% to 30%.13
Marjolin ulcer refers to a malignant degeneration arising from areas of chronic inflammation or injury of the skin, regardless of the origin of the lesion or the type of malignancy.11 An estimated 1.7% of chronic wounds undergo malignant degeneration,15 whereas Marjolin ulcers have been reported to occur in 1.6% to 23% of all patients with chronic osteomyelitis.16-18 Developing countries with limited access to medical treatment have a higher incidence of Marjolin ulcers and disease state because of the frequently delayed presentation.17,18 Marjolin ulcer most often occurs in men aged 18 to 40 years10,14,16 (Table 1). The malignant transformation takes place over the course of several years, with a latent period of 27 to 30 years,16,17,19,20 ranging from 18 to 72 years (time of presentation of osteomyelitis to malignant transformation).16,19 Acute cases have also been reported but are rare.21,22 The duration of chronic osteomyelitis represents the most important factor for malignant transformation.16 The tibia is the most frequently affected long bone,10,14,16 followed by the femur14,16 and the foot;14,16 in contrast, the bones of the upper extremity are rarely affected.14,20 In paraplegic patients, pressure sores and associated osteomyelitis are resistant to intervention and generally contribute to a steady decline in the patient’s condition.21 Radical treatment and reconstruction of the defect can be challenging and may be associated with a high mortality rate.21,22 Marjolin ulcer represents a welldescribed complication, especially in
Dr. Lowenberg or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Stryker; serves as a paid consultant to Stryker and Ellipse Technologies; and serves as a board member, owner, officer, and committee member of the Foundation for Orthopaedic Trauma. Dr. Giannoudis or an immediate family member has received royalties from Biomet; is a member of a speakers’ bureau or has made paid presentations on behalf of Synthes, Medtronic Sofamor Danek, and Olympus Biotech; serves as a paid consultant to Synthes and Olympus Biotech; serves as an unpaid consultant to Amgen; has received research or institutional support from DePuy, Synthes, and Pfizer; and serves as a board member, owner, officer, or committee member of the Orthopaedic Trauma Association, the British Trauma Society, the British Orthopaedic Association, the European Federation of National Associations of Orthopedics and Traumatology, and the Orthopaedic Trauma Association. Neither of the following authors nor any immediate family member has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Panteli and Dr. Puttaswamaiah.
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Malignant Transformation in Chronic Osteomyelitis: Recognition and Principles of Management
Table 1 Demographics and Type of Malignancya Study
No. Pts (Sex)
Age (yr)
Hwang et al23 Fairbairn and Hamilton21
1, M 1, M
79 25
Alami et al20
6, M 1, F
Lack and McKinley22
1, F
54.5 6 10.2 (38 to 71) 66
Kersh et al24 Hall et al25 Wolf et al26 Rauh et al27 Pandey et al28
1, M 1, M 1, M 1, M 1, M
62 54 60 69 65
Pandey et al28
1, M
24
Ogawa et al19 Zlowodzki et al29
1, M 1, M
60 51
Smidt et al30 Altay et al16
1, M 7, M
Puri et al31 Campodonico and Carmignani32
1, M 1, M
Site
Time Since Initial Injury (yr)
Proximal third of anterior tibia Ischial tuberosities, sacrum and femoral head, complicated with multiple pressure sores Tibia: 4 pts femur: 2 pts humerus: 1 pts Ischium
15 10 24.5 6 11.0 (9 to 40) 10 to 12
Fifth toe Greater trochanter Anterior side of proximal tibia Thumb-distal phalanx Medial side of distal third of the leg Anteromedial aspect of the upper leg Elbow Distal femur
1 14 58 10 34
50 59.5 6 3.2 (54 to 63)
Leg Ankle: 2; calcaneus: 2; forefoot: 3
40 26.9 6 14.8 (4 to 50)
40 23
Mid third of anterior tibia Hip and pelvis
21 10 15
5 1.3 (continued)
MRSA = methicillin-resistant Staphylococcus aureus, SCC = squamous cell carcinoma a Following a review of the literature, we identified 15 eligible studies (case series reporting on a total of 28 patients).16,19-32 Studies selected were original articles that fulfilled the following inclusion criteria: (1) studies enrolled adult patients with evidence of malignant transformation of chronic osteomyelitis wound (ie, Marjolin ulcer); (2) studies were published within the last 10 years; (3) adequate information was included; (4) articles were published in the English language; and (5) the full text of each article was available.
developed areas of the world in which the longevity of this patient population is extended.21,22 Marjolin ulcers predominately involve aggressive squamous cell carcinomas (SCC).10,16,19,23,29,33 Other types of malignancies associated with chronic osteomyelitis include basal cell carcinoma,10,19 fibrosarcoma,10,16,19 myeloma,10,16,19,29 10,16,19,29 angiosarcoma, rhabdomyosarcoma,10,16,19,29 fibroblastic osteosarcoma,31 adenocarcinoma,29 B cell lymphoma,16,19,29 plasmacytoma,16 malignant fibrous histiocytoma,16,29 malignant hemangioendothelioma,29 reticulosarcoma,19 and fibroblastic osteosarcoma.19,29,34
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Etiopathogenesis The exact mechanism of malignant transformation of Marjolin ulcer remains unclear and is controversial.33 The main hypothesized theory is that chronic inflammation is carcinogenic.10,15,17,20,21,33,35-37 In general, chronic inflammation favors carcinogenesis, malignant transformation, tumor growth, invasion, and metastatic spread.11,35-37 Chronic inflammatory mediators also exert pleiotropic effects on the development of cancer,11 while inflammatory cytokines may potentially lead to an altered expression of tumor suppres-
sion genes, such as tumor protein p53.9,15 Other hypothesized carcinogenic settings include (1) the lymphatic obliteration that decreases the antigen presentation to the host;17,33 (2) toxins released from the damaged tissues that are speculated to cause cellular mutations;15,21,33 (3) an immunologic etiology in which the inflamed tissues may become depleted of immunologic cells so that tumors can escape immunodetection;15,17,21,33 (4) implantation of traumatic epithelial elements that may cause a foreign-body response;15,33 (5) heredity;21,33 (6) co-carcinogen theory speculating that the original insult is not in itself carcinogenic but may activate preexisting
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Table 1 (continued ) Demographics and Type of Malignancya Tumor Size (cm)
Histologic Type
4· 7 Multi-focal tumor
SCC Moderately differentiated SCC with a highly infiltrative growth pattern and evidence of perineural and perivascular invasion Well-differentiated SCC with bone invasion: 5 cases; invasive SCC: 2 cases Well-differentiated SCC with bone invasion
Not mentioned Not mentioned
Pseudomonas aeruginosa Not mentioned Pseudomonas aeruginosa
8· 5
SCC SCC Moderately differentiated SCC, large keratinizing type Malignant fibrous histiocytoma of bone grade 4 SCC SCC (deceased pt; poorly differentiated, invasive squamous epithelial cells) High-grade fibroblastic osteosarcoma
Staphylococcus aureus Not mentioned Staphylococcus most common; most pts had mixed infections Not mentioned
Not mentioned
Undifferentiated sarcoma
Not mentioned
Not mentioned 14 1.3 · 1 · 0.3 Not mentioned 6· 2 Entire length of distal phalanx 20 · 15 20 · 7 14 · 18 Not mentioned Not mentioned Not mentioned
Pathogen Isolated
Not mentioned
Serratia marasacens and Prevotella; then MRSA and Pseudomonas Well to moderately differentiated invasive SCC Not mentioned Moderately differentiated SCC with invasion Not mentioned into skin layers Epithelioma cuniculatum (variant of SCC) b-hemolytic Streptococcus and Corynebacterius spp. Moderately differentiated SCC Pseudomonas aeruginosa; Staphylococcus aureus
MRSA = methicillin-resistant Staphylococcus aureus, SCC = squamous cell carcinoma a Following a review of the literature, we identified 15 eligible studies (case series reporting on a total of 28 patients).16,19-32 Studies selected were original articles that fulfilled the following inclusion criteria: (1) studies enrolled adult patients with evidence of malignant transformation of chronic osteomyelitis wound (ie, Marjolin ulcer); (2) studies were published within the last 10 years; (3) adequate information was included; (4) articles were published in the English language; and (5) the full text of each article was available.
neoplastic cells or make them more susceptible to other carcinogenic factors;21,33 and (7) ultraviolet rays.33 Most likely, the process of malignant transformation represents a multifactorial event having several contributing factors.21 Another factor that has been reported to contribute to the development of carcinogenesis in the host is the pan-genome or supragenome found in most accepted bacterial infections. According to the Distributed Genome Hypothesis38 that addresses chronic polymicrobial infections, the occurrence of real-time horizontal gene transfer further poses confusion to the host immune system, requiring September 2014, Vol 22, No 9
it to adapt at an inordinate rate, thus resulting in latent mutations.39,40
symptoms include hyperkalemia, weight loss associated with a reduced oral intake,25 and hyperpigmented surrounding skin.28
Clinical Features Increased pain,14,16,19-21,26-29,30,32 a foul smell,16,19,20,24,26-28,32 and increased drainage19-21,24,28,29,31 are the most common presenting symptoms of Marjolin ulcers. Other common characteristics include an enlarging or exophytic mass,14,16,19,21,24,26,31 erythema,24,29 bleeding,26,32 continued unresponsiveness to therapy,19,31,39 lymphadenopathy,16,19 and hemorrhage.19 Other, less frequently presenting
Imaging Features The malignant transformation starts from the skin or the epithelial lining of the fistula,20 and if neglected, infiltrates the bone in a permeative fashion.26 Several imaging modalities are used to detect each stage of the disease, thus aiding in the diagnosis. Periosteal changes19 and progressive bone destruction are evident on plain radiographs,19,28 with
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Malignant Transformation in Chronic Osteomyelitis: Recognition and Principles of Management
Figure 1
Figure 2
Clinical photograph demonstrating ulceration in chronic osteomyelitis.
AP (A) and lateral (B) radiographs demonstrating changes associated with chronic osteomyelitis (periosteal thickening, focal bony lysis, endosteal scalloping, loss of bony trabecular architecture, new bone apposition, peripheral sclerosis).
osteolysis seen in the more advanced stages of the disease.20,24,26,27,31 Following invasion of the bone marrow, it can becomes sclerotic26 or, conversely, medullary destruction may be evident.25 Other common characteristics seen on radiographic images include a soft-tissue mass19,25 and soft-tissue swelling.24 Serial radiographs of the affected area are useful in detecting the subtle changes that suggest malignant transformation,31 although they cannot always confirm or refute the malignancy. CT best visualizes the extent of bone involvement, and staging CT is particularly useful to detect distant metastases.19,26 MRI can assess soft-tissue involvement. Soft-tissue masses19,27 and bone marrow edema26 are the most common presentations seen on MRI; however, these changes are also seen in chronic osteomyelitis.19,27 MRI
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is also used to differentiate SCC from other types of soft-tissue neoplasms.24 It has also been reported that MRI is the modality that best correlates with the histologic findings.26 Nevertheless, there are cases in which no sign of malignancy is evident on any of the imaging modalities. As stated, osteolysis might be the only sign, especially at the initial stages of the disease; however, it is also commonly seen in an otherwise uncomplicated case of chronic osteomyelitis.28 Therefore, a high clinical suspicion is paramount in the early detection of malignant transformation.
Diagnostic Approach Diagnosis can be very challenging because only subtle changes may occur in the sequence of events in
chronic osteomyelitis (Figure 1). The combination of obtaining a detailed history and conducting a comprehensive clinical examination17 provides the physician with valuable information. In principle, patients with chronic osteomyelitis ulcers/ fistulas (Figure 2) require a close follow-up;26 any chronic wound that demonstrates characteristic changes should raise the suspicion of malignant transformation.19 Zlowodzki et al29 suggest that frozen sections and permanent pathology sections should be obtained during the initial débridement of all chronic infectious or tumorous conditions to help ensure that there is no underlying malignancy. Confirmation of a malignancy may be best achieved by obtaining biopsies at multiple sites and depths to increase the diagnostic accuracy,19 thus reducing the risk of obtaining false-negative results.28 Samples should include tissue from the sinus tract, the ulcer, and the bone.16 Some physicians advocate that biopsies should also be obtained at regular intervals during the healing
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process of every wound associated with chronic osteomyelitis, continuing until the wound is completely healed.21 The best time for obtaining a biopsy remains controversial, but most physicians recommend 3 to 4 months after initiation of treatment and when the wound has not responded to standard treatment.15 Others suggest that because of the small incidence of malignant degeneration of chronic wounds, only suspicious lesions should be biopsied.15 Once a malignancy is diagnosed, distant metastases can be ruled out with the use of staging CT, MRI, and PET.19,23,26 CT-guided biopsies may be of use in cases involving metastatic disease.25 Lymph node biopsies may also be required to show evidence of lymphatic disease;21 this is the most common site of metastasis,27 whereas a biopsy of the sentinel lymph node may be particularly useful in clinically nodenegative patients.21 Nevertheless, the presence of satellite nodes can often indicate an inflammatory reaction.20
osteomyelitis is poor, mainly because of the lack of awareness and, therefore, late diagnosis.21 When the condition is diagnosed early, the outcome following complete excision is more favorable.10 Generally, these malignancies are aggressive and have a tendency of local recurrence and lymph node metastases,10 especially with highgrade lesions.16 In patients with SCC, lymph node metastasis has been observed in 10% to 20% of patients,16 while others report rates of .40%.27 The overall prognosis is determined by the rate of lymph node metastasis and distant metastasis,16,26 with most of the metastases presenting within the first 18 months.27 Patients with no metastatic disease during the first 3 years usually have a good prognosis.27 The presence of lymphatic spread or distant metastasis reduces the survival rate to 35% to 50%,20 whereas the overall mortality has been reported to be as high as 9.6%.14
Management Differential Diagnosis The features of osteomyelitis (ie, lytic lesions, cortical destruction) may resemble common features reported in several other conditions, thus making it even more challenging to distinguish between these conditions. Further evaluation and histopathologic examination is of paramount importance to allow for early identification and appropriate treatment. Other skin conditions involved in the differential diagnosis of SCC include basal cell carcinoma, Bowen disease, cutaneous granulomas, psoriasis, eczema, and keratoacanthomas.24
Prognosis The prognosis of malignant transformation that results from chronic September 2014, Vol 22, No 9
The definitive treatment of choice as suggested by most clinicians has been amputation proximal to the tumor16,20,24,28 (Table 2). Although this is an aggressive action, amputation offers a relatively simple solution for eradicating both the chronic osteomyelitis and the malignancy. Moreover, it provides a faster and safer recovery in advanced complex cases.20 Recently, wide complete local excision has also been proposed in selected patients and before any distant metastasis is evident.15,19,23 When the histologic type of a Marjolin ulcer is SCC, it has been suggested that the resection margin should be at least 2 cm, along with a clear deep margin.23 The use of Mohs micrographic surgery has also been reported in the absence of distant metastases and lymph node involve-
ment.15 With this technique, the tumor is followed microscopically through serial sections, thus ensuring complete eradication.15 Following wide resection, free-tissue transfer may be used to cover the soft-tissue defect, whereas free vascularized osseous transfer or bone transport via distraction osteogenesis can be used to restore the segmental bone defect.23 When surgical excision of the lesion is not possible, amputation should be considered.17 In the presence of paraplegia and associated chronic pressure sores in the sacral and ischial regions, radical surgical management with hemipelvectomy and extensive flap reconstruction has been proposed.21,22 Because of the late diagnosis and hence poor prognosis, the need for interventions necessary to prevent the malignant transformation is stressed.21,22 Additionally, the patient should be screened for lymphadenopathy and distant metastases. However, it remains controversial whether regional lymphadenectomy is required16 because lymph node enlargement is often the result of inflammatory causes and subsides following treatment.16 However, if lymph node enlargement persists for 6 to 12 weeks after amputation, surgical treatment is warranted.15,16 Adjuvant chemotherapy25 and/or radiation therapy19,25,28 may be useful in the presence of inoperative metastatic disease21,27 and highgrade tumors.31 Finally, the patient should be seen for regular follow-up to examine for any signs of local recurrence, palpable regional lymph nodes, or evidence of distant metastases.23
Summary Malignant transformation as a result of chronic osteomyelitis represents
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Malignant Transformation in Chronic Osteomyelitis: Recognition and Principles of Management
Table 2 Staging, Treatment, and Outcome Study
Metastases (Gradinga)
Lymph Node Status
Hwang et al23
None affected
None (N0M0)
Fairbairn and Hamilton21
None affected
None (N0M0)
None affected One lymph node positive to SCC metastasis 1 residual bilateral pelvic and inguinal lymphadenopathy on staging CT None affected None affected None affected
None (All patients N0M0) Lungs 1 extensive metastatic abdominal disease (N1M1)
Alami et al20 Lack and McKinley22
Kersh et al24 Hall et al25 Wolf et al26
Ogawa et al19
Second operation: 1 of 29 lymph nodes was positive to SCC 1 single axillary mass 7 · 8 cm (inflammation without malignancy) None affected Inguinal lymphadenopathy; biopsies showed it was reactive None affected
Zlowodzki et al29 Smidt et al30 Altay et al16
One lymph node was positive to malignant fibrous histiocytoma Only reactive response 4 patients (including deceased pt)
Rauh et al27 Pandey et al28 Pandey et al28
Puri et al31 Campodonico and Carmignani32
2-3 palpable inguinal nodes (1 · 1 cm), but were not considered to be significant Spread to pelvic lymph nodes
None (N0M0) Both lungs (N0M1) None (N0M0)
Tip of the small finger 1 flexor tendon sheath 1 lungs (N1M1) None (N0M0) None (N0M0) None (N0M0)
None (N1M0) None (N0M0) In 1 pt, deceased (N0M0, 3 pts; N1M0, 2 pts; N1M1, 1 pt) None (N0M0) None (N1M0) (continued)
a
NM staging of soft-tissue sarcomas: N (describes lymph nodes metastasis): N0 = sarcoma has not spread to neighboring nodes, N1 = sarcoma has spread to neighboring nodes. M (describes distant metastasis): M0 = sarcoma has not metastasized, M1 = sarcoma has metastasized to distant organs and/or tissues MCPJ = metacarpophalangeal joint, MTPJ = metatarsophalangeal joint, SCC = squamous cell carcinoma
a relatively rare and late complication. Its incidence appears to be declining in countries with more modern health care, but it remains a problem in developing countries. The interval between the original bacterial infection and malignant degeneration is, in
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most cases, many years and often can be decades. Clinical suspicion should be high in every case of chronic discharging osteomyelitis, combined with a low threshold of obtaining wound biopsies, especially with the onset of new clinical signs. The most
effective prevention is the definitive treatment of the osteomyelitis, with adequate débridement and wide excision of the affected area and early reconstruction with the use of modern limb salvage and reconstruction methods.
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Michalis Panteli, MD, et al
Table 2 (continued ) Staging, Treatment, and Outcome Type of Treatment
Recurrence (Pts Deceased)
Follow-up (mos)
Latissimus dorsi free flap 1 free vascularized fibula (from contralateral side) Abdomino-perineal resection and colostomy; radical excision of sacral and ischial pressure sore SCC; débridement of osteomyelitic left hemipelvis; disarticulation and excision of femoral head, femur, tibia, and fibula; and complete lower limb myocutaneous fillet flap reconstruction, pedicled on the femoral vessels Amputation in 6 pts; 1 pt refused amputation Hemipelvectomy Fifth toe amputation through MTPJ, followed by wide resection of the affected skin Not mentioned
18
No (No)
Not mentioned
Not mentioned (No)
60 3 16
No (No) Extensive metastatic disease (Yes) No (No)
Not mentioned
Not mentioned (Not mentioned) No (No) 1 yr later and again 4 mos after first recurrence (Yes)
Knee exarticulation 10 Initially amputation through the distal portion of the proximal 22 phalanx; then wide of the proximal phalanx down to the MCPJ. First relapse: Wide resection of the mass including thumb and index finger ray amputations 1 radical axillary dissection 1 radiation therapy. Second relapse: Radiation therapy 1 palliative small finger ray amputation. Below-knee amputation 24
No (No)
Below-knee amputation Amputation at the midshaft of the humerus (1) Irrigation and débridement of the draining sinus (before histology); (2) elective reconstructive surgery; (3) irrigation and débridement of the femur with resection of the distal femur approximately 15 cm above the knee for staged reconstruction 1 cement spacer; or (4) hip disarticulation 1 chemotherapy. Supracondylar leg amputation Below-knee amputation: 4 pts; Syme amputation: 2 pts; wide resection: 1 patient. Lymphadenectomy: 4 pts. The patient with distant metastasis also had radiation therapy.
Not mentioned 5 27
No (No) No (No) No (No)
12 68 6 42 (22 to 147)
No (No) 1 pt: local recurrence 19 mos after primary amputation; required a more proximal amputation (died)
Below-knee amputation
Not mentioned
Not mentioned (Not mentioned)
Wide excision
3
Pt deceased 3 mos postop (Yes)
a
NM staging of soft-tissue sarcomas: N (describes lymph nodes metastasis): N0 = sarcoma has not spread to neighboring nodes, N1 = sarcoma has spread to neighboring nodes. M (describes distant metastasis): M0 = sarcoma has not metastasized, M1 = sarcoma has metastasized to distant organs and/or tissues MCPJ = metacarpophalangeal joint, MTPJ = metatarsophalangeal joint, SCC = squamous cell carcinoma
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