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Bone infarct transformation into undifferentiated pleomorphic sarcoma in sickle cell disease: A case report

Highlights • Sickle cell disease pathophysiology.• Natural progression of a pre-existing bone infarct.• Malignant transformation of a pre-existing bone infarct.• A rare case describing malignant transformation of a pre-existing bone infarct in a known sickle cell anemia patient into malignancy in specific undifferentiated pleomorphic sarcoma.


Introduction
Osteonecrosis is a common finding in sickle cell disease (SCD). This is mostly related to vaso-occlusion and sickling of red blood cells causing bone ischemia. It is estimated to affect 10% of sickle cell disease patients [1,2]. The process may appear at any part of the skeleton and long bones. It is agreed that when they affect the epiphysis, then it is called "avascular necrosis", whereas in the metaphysis and diaphysis, it's commonly called "bone infarct" [3].
Although rare, bone infarct associated sarcoma (BIAS) has been reported in the literature [4][5][6][7][8][9]. In a sickle cell anemia patient, this transformation is much less likely. In this report, we present a known case of sickle cell disease, with a known primary proximal femur bone infarct, that has transformed into undifferentiated pleomorphic sarcoma.
The patient was informed that data concerning this case would be submitted for publication, and he agreed. This case was reported in accordance with the SCARE Guidelines [10].

Case report
A 40 years old male, known to have sickle cell anemia, was admitted to King Faisal Specialist Hospital and Research Center with a left proximal femur impending pathological fracture, on November 2019. Early on October 2016, he was evaluated for right hip pain and diagnosed with avascular necrosis (AVN) of right hip (Fig. 1).
Surgical history, family history, and psychosocial history were unremarkable. So, the patient was offered total hip replacement surgery, but he preferred to go for conservative management. During his follow up MRI with contrast on January 2018 indicated serpiginous bone infarcts involving the right proximal femoral shaft as well as left femoral head and intertrochanteric region demonstrating high T2 signal intensity and low T1 signal intensity (Fig. 2).
The patient remained on regular follow up with a stable condition until he presented on November 2019 with increasing pain in the left thigh and decreased in the level of activity, there was no palpable masses alongside a left hip painful range of motion with intact distal neurovascular status. X-ray showed osteolytic lesion, involving the left femoral sub-trochanteric area and the lateral cortex, with a picture of an impending fracture (Fig. 3).
Further skeletal survey showed multiple scattered bone infarcts, mainly at the diaphysis of both lower extremities, as well as, bilateral shoulder and hip joints AVN.   intertrochanteric area with cortical destruction. These imaging features highly indicate malignant transformation of the osteonecrosis (Fig. 4).
Systemic staging in the form of CT chest with contrast was free of any metastatic lesion and bone scan showed radiotracer uptake at the left intertrochanteric region consistent with the aggressive lesion. Radio Tracer uptake was also observed at the left distal femur, left proximal tibia and right proximal tibia, all of which represent bone infarcts (Fig. 5).
Open biopsy of the left proximal femur lesion displayed malignant spindle/epithelioid neoplasm consistent with high-grade sarcoma, undifferentiated pleomorphic sarcoma (Fig. 6). Laboratory investigations were also consistent with patients' condition of SCD. After adequate preparation, the patient was taken for resection of the proximal femur and reconstruction with mega-prosthesis (Fig. 7). The surgery was done by the senior authors (MS and RP). Histopathology analysis of the specimen showed high-grade pleomorphic sarcoma consistent with malignant fibrous histiocytoma of bone, all margins were free of tumor.
Post-intervention considerations included referring the patient to medical oncology department where adjuvant chemotherapy was started. He is still under chemotherapy treatment up to the time of this report. His overall health status is fair, started weight bearing without any complications related to surgery, and no local recurrence up to date. CT chest in follow up on January 2020, showed no evidence of metastatic disease.
The patient was satisfied about his general medical condition and surgical treatment that he received. The patient is being followed every 3 months with proper imaging.

Discussion
Bone infarct, also known as AVN of the bone, are commonly seen in orthopedics surgery practice and mostly involving the hips and the knees [4]. Development of bone infarct might be idiopathic and also has been linked to several medical and environmental conditions including sickle cell disease, sickle cell trait, Gaucher disease, Cushing disease, pancreatitis, collagen diseases, pregnancy, steroid  therapy, radiation exposure, diving and caisson disease, high room pressure exposure, mine working, and alcohol abuse [5].
Bone infarct starts as an acute process of bone ischemia. In sickle cell disease, it is linked to vaso-occlusive crises and sequestration of red blood cells in the bone marrow causing pain. This acute inflammatory process will eventually develop tissue ischemia [11].
The transformation of the bone infarct in this reported case of a sickle disease patient, into a high-grade sarcoma, is very rare. To the best of our knowledge, only one other case of a patient with known sickle cell disease and a bone infarct transformation to bone sarcoma, was reported in the literature [6].
Sarcomas arising from a subsequent existing bone infarct, are extremely uncommon. It was first documented by Furey et al. reporting a fibrosarcoma in 1960 [8]. Since that time, few infarct-associated sarcomas have been reported, with diverse histopathological types including malignant fibrous histiocytoma, osteosarcoma, angiosarcoma, fibrous sarcoma and epithelioid hemangioendothelioma. Secondary sarcoma originating from a pre-existing bone infarct are usually found during the sixth decade of life, mostly men, and it has been reported that 60% of the cases from the knee and most of them are MFH [4]. Over the decades, it has been proven that sarcomas can arise from infarcts of the long bone, the incidence of which has been reported to be 1% of all diagnosed bone sarcomas [12].
In relation to haemoglobinopathies, the majority of bone infarct lesions transformations into sarcoma reported are linked to sickle cell trait (SCT). Sickle cell trait patients has one sickle beta globin  gene and one normal gene, making it a heterozygous condition, while sickle cell disease is a homozygous condition with two sickle beta globin genes. Patients with SCT are less symptomatic than SCD patients. Bone infarct are more common in sickle cell disease than in sickle cell trait [13,7]. In reviewing the history of related studies, we have found four cases of sickle cell trait with bone infarct associated sarcoma, and one case of sickle cell disease indicating that bone infarct associated sarcoma are more common in SCT than SCD. All of the five cases occurred in males. Doung [7] related this gender predominance to working conditions including dysbaric exposures. In our case the patient was never exposed to pressure related environment.
Sickle cell disease and trait are seen more in black race, all the five cases mentioned above also had this in common. Our reported case is of a dark-skinned man and not considered of a black race background. The age of diagnosis had ranged from 20 to 69 years old. Bone infarcts are usually asymptomatic, and it's hard to predict the exact timing of which the process was first developed. Taking this in consideration, the exact timing of transformation of the infarct into sarcoma is hard to predict.
The exact mechanism of transformation is yet to be investigated. It was hypothesized by Mirra that the reparative process leads the transformation into sarcoma in the bone infarct lesions [6]. This process might be more active in SCT than in SCD which could be the reason of having more bone infarct associated sarcoma in SCT than in SCD. The type of sarcoma of all patients varied. There were two cases of Malignant Fibrous Histiocytoma of Bone (MFHB) in SCT, one case of osteosarcoma and high grade of pleomorphic osteosarcoma in SCT, and the other case of SCD, had a fibrosarcoma (Table 1).
In the case of SCD with BIAS reported by Mirra, the patient was a 26 years old black male. His lesion was located in the distal tibia and management consisted of radiation therapy then the Table 1 Displaying other cases that showed an infract developing into a malignancy.
Author leg was perfused with phenylalanine mustard and actinomycin D followed by "above knee amputation". Unfortunately, the patient developed aggressive lung metastatic lesion and died 15 months after his surgery [6]. It has been reported that most of these sarcomas are malignant fibrous histiocytoma (MFH), which is a rare primary sarcoma of the bone. On the other hand, osteosarcoma, which is the most common primary bone sarcoma, has been rarely reported in a pre-existing bone infarct [9].

Conclusion
In our experience at King Faisal Specialist Hospital and Research Center, we reviewed 1900 cases of bone sarcoma and this is the only case of BIAS arising in SCD.
The pathophysiology behind the sarcoma arising from bone infarct is still not fully understood. All cases reviewed were managed differently. Although rare one should have a high index of suspicion when encountering bone infarct that undergoes atypical changes with time.
In reporting this case we hope that further attention is provoked in the medical community to report such cases when encountered; and accordingly, evidence of such associations can be established alongside a solid evidence-based treatment algorithm.

Declaration of Competing Interest
The authors report no declarations of interest.