Marjolin’s Ulcer of the Tibia With Pelvic Lymph Node Metastasis

Abstract

Marjolin’s ulcer, a form of squamous cell carcinoma, is a rare complication of a chronic wound infection. To date, there have not been any detailed reports of lymphatic spread of Marjolin’s ulcer from an extremity. This report describes a 44-year old male with a history of an open tibia fracture at age 15, who presented with chronic osteomyelitis, increasing bloody wound drainage, and an enlarging vascular exophytic masses in the region of drainage. Biopsy of the mass showed squamous cell carcinoma. Initial staging with computed tomography (CT) was negative for metastatic disease. Six months after undergoing a below-knee amputation (BKA), the patient developed an enlarged lymph node in the left inguinal area. His re-staging CT and biopsy of inguinal node confirmed the presence of metastatic squamous cell carcinoma. The patient was subsequently treated with inguinal node dissection and adjuvant radiation therapy. At 2.5 years follow-up, the patient remains disease-free. Our case illustrates the importance suspecting squamous cell carcinoma in patients with chronic infections and diligent follow up for patients with Marjolin’s ulcers.

Introduction

Marjolin’s ulcer was was first coined by a French surgeon named Jean-Nicholas Marjolin as “ulcers canceroides” in his classic essay in 1828¹. These lesions generally arise after a latency period of years from the original injury, and it is hypothesized that they result from a malignant degeneration caused by chronic inflammation in non-healing wounds^2,3. Potential etiologies include burn eschars, pressure sores, venous stasis ulcers, traumatic wounds, osteomyelitis, and fistulas⁴. These patients present with symptoms refractory to treatment and include pain, bleeding, and growing exophytic mass^5,6. Once malignant transformation occurs, these lesions can invade into the deep tissue and surrounding structures, requiring aggressive surgical treatment. To our knowledge, there has not been any previous detailed reports of lymphatic spread of Marjolin’s ulcers. In this paper, we present a case report of a 44-year old male with squamous cell carcinoma transformation and local metastasis from a chronic sinus tract and osteomyelitis of the left tibia.

Clinical Case

A previously healthy 44-year old gentleman presented to the orthopaedic tumor clinic for evaluation of an enlarging exophytic mass of his left leg. He had a history of a farming accident at the age of 15 involving his bilateral lower extremities, including an open left pilon fracture and ipsilateral tibia plateau fracture. He was initially treated with an open reduction internal fixation and skin grafting. His post-operative course was complicated by a necrotic left leg wound that required muscle excision and left leg venous bypass. He also had recurrent infections requiring multiple incisions and drainage as well as multiple courses of intravenous (IV) antibiotics. About ten years later, he underwent a left transmetatarsal amputation, which at that time relieved his persistent drainage.

Twenty-eight years after his initial injury, he presented to his primary care physician (PCP) due to a recurrence of serosanguinous drainage from the fracture wound site at his anterior distal leg. He was subsequently treated with IV antibiotics for several months. During a routine follow-up appointment with his PCP, an exophytic mass was discovered on the left tibia and he was referred to a local orthopedist. Plain films at that time revealed an expansile 5.1 cm lytic lesion in the distal left fibular diaphysis with lateral soft tissue swelling and slightly sclerotic bony margins concerning for malignancy. Given these findings, he was referred to an orthopaedic oncologist.

At his initial orthopaedic oncology clinic visit, physical exam revealed a 2.5 by 2.5 cm circular friable exophytic mass on the anterolateral middle of the left tibia with a separate proximal draining sinus (Figure 1). He was neurovascularly intact with no other abnormalities noted on physical exam. Labs showed elevated inflammatory markers as follows: white blood cell count (WBC) 8.6 with a normal differentiation, erythrocyte sedimentation rate (ESR) 42, and C-reactive protein (CRP) of 7.4. Repeat plain radiographs showed an interval increase in size of the lytic fibula diaphyseal lesion (Figure 2). Magnetic resonance imaging (MRI) showed a 4.7 × 3.4 cm2 lytic lesion in the left fibula with a significant soft tissue component that eroded through the cortex (Figure 3). A computed tomography (CT) scan of the chest/abdomen/pelvis was negative for any extraosseus primary malignancy or regional lymph node metastasis. He subsequently underwent an incisional biopsy in the operating room, and histology showed an invasive, moderately-differentiated (T4N0M0) squamous cell carcinoma consistent with a Marjolin’s ulcer (Figure 4) Wound cultures obtained in the operating room grew Prevotella buccae, Haemophilus parainfluenzae, Actinomyces odontolyticus, Corynebacterium simulans, and Moraxella nonliquificiens.

Figure 1:

exophytic left distal anterior leg mass

Figure 2:

Radiographs of the left leg

(A) Initial plain radigoraphs obtained at an OSH (B) 6 months later xrays show an increase in the lytic fibula diaphyseal lesion.

Figure 3:

MRI of the left leg

(A) T2 sagittal, (B) T1 sagittal , and T2 axial images of the left tibiafibula reveal a 4.7 × 3.4 cm2 lytic lesion in the left fibula with soft tissue extension

Figure 4:

Incisional Biopsy Pathology

(A)Low and (B) High-powered pathology slides demonstrating a moderately-differentiated squamous cell carcinoma

Given the invasive nature of the patient’s Marjolin’s ulcer without evidence of metastasis, he underwent a left below knee amputation (BKA). Intraoperatively, he was noted to have extensively fibrotic tissue in his deep posterior compartment without evidence of gross purulence. Operative gross pathology results showed a 4.2 cm diameter SCC mass that invaded 3.2 cm deep with negative 3.9 cm tissue margins. He was discharged with a 6 week course of IV daptomycin 500 mg and IV ertapenem 1 gm. At the 4 month post-operative follow-up, the patient was doing well and reported no complications.

Five months following his BKA, the patient presented to his PCP with a small bump on the lateral aspect of his BKA stump and a new mass in his left groin. He denied any constitutional symptoms and his ESR and CRP were 20 and 2.3, respectively. A 5 mm punch biopsy of the distal stump lesion was negative for SCC. Re-staging with CT scan of the chest/abdomen/pelvis and positron emission tomography-computed tomography (PET-CT) scan revealed a 2 cm left inguinal lymph node without evidence of organ metastasis (Figure 4). A fine needle aspiration (FNA) was performed of the lymph node was positive for metastatic SCC. Due to the presence of regional metastatic disease, he was referred to a surgical-oncologist and underwent an inguinal lymph node resection with adjuvant radiation therapy 7 months after his BKA. His intraoperative pathology showed 2 macro-metastatic nodes, the largest being 3.6 cm, with 6 other negative nodes. Following his inguinal nodal dissection, he completed 6 weeks of adjuvant radiation therapy (6,600 cGy in 33 fractions). Surveillance CT scans of the chest/abdomen/pelvis at 8 and 12 months postoperatively were negative for new lesions and did not show any recurrence of cancer.

Figure 5:

Regional lymphatic metastasis

Axial image of a (A) CT abdomen and (B) PET-CT scan reveals a 2 cm left inguinal lymph node

Discussion

This case study presented a young healthy male with malignant transformation of a chronic infection and subsequent regional lymph node metastasis of a Marjolin’s ulcer. Marjolin’s ulcer is a rare entity and is estimated to occur in 1.7% of all chronic wounds⁷ with a mean latency of 28.7 years⁴. A literature review of 443 cases showed that the most common etiology for Marjolin’s ulcer is a burn wound (76.5% cases), followed by traumatic wounds (8.1%), venous stasis ulcers (6.3%), and osteomyelitis (2.6%),⁴. Another study showed that up to 23% of patients with chronic osteomyelitis can undergo this malignant transformation⁸. Although the exact pathophysiology is largely questioned, the prevailing theory is that it arises from a state of chronic inflammation and cell proliferation². This subsequently increases the expression of proto-oncogenes in the epithelial cell line, leading to self-sustainability and ability to evade apoptosis^{2, 9}. Early recognition and management is key to preventing long-term complications, such as local tissue destruction and metastatic spread⁹. Additionally, chronic avascular scar tissue limits the ability of immune cells to suppress mutated cells during oncogenic development⁴.

The etiology of our case’s malignant transformation was from chronic osteomyelitis and chronic sinus tract infection developed from an open tibia shaft fracture and fixation. Osteomyelitis is an ancient disease first described by Hippocrates around 460-370 BC¹⁰. Officially published by Bromfield in 1773, osteomyelitis is an inflammatory process that can lead to progressive bone destruction^{5, 11}. Radiographs and advanced imaging assists with the extent of lytic lesion, cortical involvement, and the presence of a sequestrum or involucrum^{5, 12}. The Cierny-Mader classification system for osteomyelitis incorporates four anatomic types with three physiologic classes to define 12 clinical stages (Table 1)¹³. These clinical stages depend on the condition of the host, the anatomic site of infection, functional impairment caused by the disease, and the extent of bony necrosis^{13, 14}. Using the Cierny-Mader classification aids in treatment, with more aggressive debridement, revascularization, optimization of host co-morbidities, and potential bone stabilization for higher grade lesions¹². Our case report would be designated as diffuse type 4A chronic osteomyelitis of the left fibula in an immunocompetent host due to direct inoculation from the time of his open tibia farm injury. Although a rare occurrence, malignancies found within chronic wounds are well-documented^15-17.

Table 1:

Cierny-Mader classification of adult osteomyelitis

Anatomic type
Type 1	Medullary osteomyelitis (nidus is endosteal). No dead space management. Etiology often hematogenous, post-intramedullary rod.
Type 2	Superficial Osteomyelitis. Limited to surface of bone. No dead space management but needs soft tissue coverage
Type 3	Localized osteomyelitis. Full thickness of cortex. Complex dead space management, simple osseous stabiliization
Type 4	Diffuse osteomyelitis. Circumference of cortex. Biomechanically unstable. Complex dead space and osseous management.
Physiologic host
A Host	Normal host. Normal immune system. Normal vascularity.
B Host	Bs: systemic compromise Bl: local compromise Bsl: systemic and local compromise
C Host	Treatment morbidity worse than present condition with low prognosis for cure.

Adapted from: Cierny, G., 3rd, J.T. Mader, and J.J. Penninck, A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res, 2003(414): p. 7-24.

The tibia is the most common location for osteomyelitis and the incidence approaches 10% in open traumatic injuries^18,19. The most common pathogen is Staphylococcus aureus²⁰. Other common pathogens include Staphylococcus epidermidis, gram-negative bacilli, and anaerobes²¹. Biolfilm formation by bacteria represents a protective layer that is the key to the pathophysiology of chronic osteomyelitis²². Catalase is secreted into this protective layer by bacteria, neutralizing the hydrogen peroxide generated by host neutrophils²³. Additionally, this biofilm layer allows for bacteria to adhere to bone, aggregate, and communicate with each other while evading host immune cells. Chronic osteomyelitis is characterized clinically by recurrence of pain in a patient with a history of osteomyelitis and swelling in association with a draining sinus²⁰. These symptoms are similar to malignant transformation.

Clinically, Marjolin’s ulcers present with increased pain, ulceration, fibrotic zones, bleeding, and irregular margins²⁴. Our patient presented with an exophytic left leg mass with chronic serosanguinous wound drainage. The evaluation of Marjolin’s ulcer includes clinical evaluation, inflammatory labs, plain radiographs and MRI imaging to assess the extent of the lesion⁵. Properly staging Marjolin’s ulcers includes using CT imaging and the American Joint Committee on Cancer (AJCC) classification system²⁵. Careful planning for tissue biopsy is necessary to ensure an accurate and timely diagnosis while avoiding complications²⁶. Histologically, our case report was found to have moderately-differentiated SCC (T4N0M0). SCC is the most common variant of Marjolin’s ulcer, accounting for up to 96% of cases²⁴. However, other malignancies such as fibrosarcoma, myeloma, lymphoma, plasmacytoma, angiosarcoma, rhabdomyosarcoma, and malignant fibrous histiocytoma have also been reported^{8, 27}. Histologic features of squamous cell carcinomas include atypical keratinocytes, increased nuclear pleomorphism, abnormal keratinization, and frequent mitotic figures. The choice of treatment is ultimately guided by having a thorough evaluation.

The discovery of regional metastasis in our case study added significant complexity in his Marjolin’s ulcer treatment. Cutaneous squamous cell carcinomas have a relatively low rate of metastasis, ranging from 0.5-3.0%¹⁵. However, those arising from invasive Marjolin’s ulcers have metastasis rates of 20-30%²⁸. Risk factors for metastatic SCC include thickness >2mm, Clark level ≥IV, perineural invasion, and poorly or undifferentiated histologic grade²⁵. In Kerr-Valentic’s case series of 10 patients with Marjolin ulcer reported one patient that developed metastasis into a sentinel pelvic lymph node. Eastman et al published a separate case series of patients with Marjolin’s ulcers secondary to upper extremity burn scars and found that 4 out of 5 cases had positive lymph nodes for occult metastasis despite not having clinical symptoms²⁹. Lack published a case report of distant metastasis of a Marjolin ulcer to the inguinal lymph nodes and lung in a paraplegic patient with recalcitrant pelvic osteomyelitis and decubitus ulcer³⁰. Despite these cases, our report illustrates the first detailed report of symptomatic lymph node metastasis for Marjolin’s ulcer secondary to chronic long bone osteomyelitis.

The treatment of Marjolin’s ulcer is complex and depends on the extent of the disease. Localized Marjolin’s ulcers are treated wide resection with 2 to 4 cm margins²⁴. For more invasive cases, amputation proximal to the tumor is advocated⁵. Radical hemipelvectomy has been described in the paraplegic population with malignancy of more proximal axial lesions^{30, 31}. The treatment for regional metastasis is surgical dissection with adjuvant radiation therapy³². The dose of adjuvant radiation is 45-55 Gy in daily fractions of 2.0-2.5 Gy³³. In contrast, if distant metastasis is present, first-line treatment is chemotherapy³². Despite having moderately-differentiated SCC and adequate surgical margins after a BKA, our patient developed regional metastatic disease. De Lima Vazquez showed that the survival of trunk and extremity T3N0M0 and T4N0M0 SCC with regional lymph node recurrence was not significantly different to patients without lymph node recurrence (34.1% and 43.3%, respectively)³⁴. De Lima Vazquez did show that higher grade T4 lesions had worse 5-year survival than T3 lesions (24.2% and 48.7%, respectively). Our patient developed metastatic disease to his regional lymph nodes despite having a BKA of his invasive tumor. Following his subsequent superficial inguinal node dissection, the patient completed a 6-week course of adjuvant radiation, with a total of 6,600 cGY in 33 fractions. He was found to be disease-free at his 2.5 year follow-up.

Conclusion

Marjolin’s ulcer is a rare sequalae of chronic wound infection and inflammation. Patients often presenting after a latency period with increased pain, exophytic mass, and drainage. In the absence of obvert clinical symptoms, progressive osteolysis on serial plain radiographs may be the only imaging sign, and a high clinical suspicion is warranted. Despite not having any signs of metastasis on presentation, Marjolin ulcers of the extremity have the potential risk of metastasis. After undergoing surgical dissection and adjuvant radiation of his regional inguinal lymph nodes, our patient has remained disease-free at 2.5 years surveillance. Our case illustrates the importance of performing an extensive workup and diligent follow up for the proper diagnosis and management of a Marjolin’s ulcer.