Two Cancers Arising from Different Mesenchymal Origins: An Unexpected Connection over Time and Space

Sarcomas are rare tumours, accounting for 1% of all malignancies. They are histologically diverse, presenting with more than 50 different subtypes. Sarcoma can be broadly divided into two categories—soft tissue sarcoma and bone sarcoma. Extraskeletal osteosarcoma is a unique subtype which is histologically similar to bone osteosarcoma but resides within soft tissue and has no attachments to bone. We present a rare case of a patient who initially presented with an extraskeletal osteosarcoma that was complicated by a chronic chest wall sinus and lymphedema of the left arm. He later developed enlarging left chest wall nodules at the same region that were proven to be dedifferentiated liposarcoma on biopsy 20 years later. We examine the occurrence of both extremely rare diseases of differing pathologies over the same site but separated by an extraordinarily long interval, and possible new associations to account for this phenomenon.


Introduction
Sarcomas are rare and uncommon tumours, representing 1% of adult malignancies [1]. They are a heterogeneous group of tumours of mesenchymal origin that can occur anywhere in the body. Sarcomas are broadly divided into two catego-ries-soft tissue sarcoma and bone sarcoma, of which liposarcoma and osteosarcoma are the most common histological subtypes respectively.
Extraskeletal osteosarcoma is a unique subtype of sarcoma, presenting with similar histology to that of osteosarcoma but lies within soft tissue and is not attached to any bones [2]. It represents approximately 1% -2% of all soft tissue sarcomas, and behaves aggressively, carrying mortality rates up to 80% [3]. Extraskeletal osteosarcomas are different from its primary counterpart of osseous origin-it occurs rarely in the younger population, and are poorly responsive to chemotherapy, with local and distant failures in more than 80% of those affected. Disease-free intervals have been found to range from two months to ten years [4]. Specifically, primary thoracic extraskeletal osteosarcoma is even rarer, and only 60 cases have been reported to date with the most common presentation coming from the lungs. The prognosis is usually extremely bleak, as the majority of patients reported had demised within months due to rapid disease progression, and overall survival at 1 year stands only at 41.8% and decreases to 22.3% at 5 years [5].
Herein, we report an interesting case of a patient who underwent resection for extraskeletal osteosarcoma 20 years ago and recently presented with a dedifferentiated liposarcoma at the same site.

Case Summary
Our patient is an 81-year-old Chinese male with comorbidities of hypertension and hyperlipidemia and a significant smoking history. He previously received treatment in another hospital for a left chest wall extraskeletal osteosarcoma for which he underwent wide excision and reconstruction with mesh and latissimus dorsi flap in 1997. He did not receive further adjuvant treatment. He remained well and disease-free until 2016 when he noted a persistent chronic chest wall sinus as well as left upper limb lymphedema that had failed conservative management. Computed tomography scan of his chest showed a 2.7 cm soft tissue thickening over the left anterior chest wall surgical site with no evidence of pulmonary metastasis or vascular obstruction. Clinical examination revealed no visible or palpable nodules, and incisional biopsy of the chest wall sinus proved to be inflamed granulation tissue with no evidence of malignancy or any infective organisms. He declined further investigations for possible disease recurrence then and only consented to treatment for the left upper limb lymphedema. He underwent left upper limb lymphovascular anastomosis in 2017 with good results. A repeat computed tomography scan of his chest done in 2018 showed interval stability of the soft tissue density, as well as oedematous changes present over the left anterior and lateral chest wall muscles. There were no overt masses detected. However

Discussion
Among soft tissue sarcomas, liposarcoma is the most common and accounts for approximately 20% of all cases [6]. These tumours affect adults with a peak incidence at around 60 years of age. About 10% progress to dedifferentiated liposarcomas and is most commonly non-lipogenic and pleomorphic. Heterologous differentiation can occur in 10% of dedifferentiated liposarcomas and present with myogenic, osteo-or chondrosarcomatous or angiosarcomatous components. Extraskeletal osteosarcoma is a rare entity that accounts for 1% -2% of all soft tissue sarcomas and 6% of all osteosarcomas. They too occur typically in the elderly with a predilection to the extremities and retroperitoneum. It is a malignant mesenchymal tumour that directly produces neoplastic osteoid or bone and diagnosis requires a careful exclusion of heterologous osteosarcomatous differentiation arising in a variety of malignant neoplasms. This is an interesting case whereby the surprise diagnosis of dedifferentiated liposarcoma in this current instance raises several unique and rare possibilities; whether the current presentation is a recurrence linked to the previous history of extraskeletal osteosarcoma, or a de novo occurrence of a second primary malignancy arising from cells of a different mesenchymal origin. Another possibility could be a misdiagnosis in the index presentation, where for instance, the initial tumour could have been a dedifferentiated liposarcoma all along, but only the predominant osteosarcomatous component was reported.
To our knowledge, there are no published anecdotes of two different primaries of these unrelated mesenchymal cell types, arising in the same patient at the same site spaced twenty years apart, which makes this novel case noteworthy. One predisposing factor which could have led to the development of a secondary malignancy is the chronic inflammation from the persistent sinus tract or upper limb lymphedema. However, what is reported in literature so far have been lymphangiosarcomas such as in the case of Stewart-Treves syndrome [7], and no association with dedifferentiated liposarcoma has been demonstrated before.
Alternatively, if this new tumour is a recurrence arising from his initial disease, the extremely long disease-free interval and the disparate mesenchymal

Conclusion
This case emphasizes the need for continued vigilance in the surveillance of sarcoma patients as the disease may have an unprecedentedly long disease-free interval. More importantly, it also exposes the gaps in our current understanding about the behavior of osteosarcomas and dedifferentiated liposarcoma as the temporal sequence of this presentation runs contrary to their established natural history. More can be done to expand the role of molecular markers to distinguish the various subtypes so as to identify the exact mesenchymal cell of origin for these rare tumours and determine the optimal treatment required.

Conflicts of Interest
The patient provided written informed consent for the publication of this case report and its accompanying images.