Dedifferentiated Low-Grade Surface Parosteal Osteosarcoma into a High-Grade Osteosarcoma: Case Report and a Brief Review of the Literature

*Corresponding author: Mohamed Aziz. Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Dedifferentiated Low-Grade Surface Parosteal Osteosarcoma into a High-Grade Osteosarcoma: Case Report and a Brief Review of the Literature John Hanna 3, Jennifer Paz 2, Sandhia Senthilnathan 2, Elizabeth Sanchez 4, Phillip Pearson 5, Jessica Jahoda 1, 6 and Mohamed Aziz 1, * 1 Research Writing and Publication (RWP), LLC, NY, USA. 2 American University of the Caribbean School of Medicine, Sint Maarten. 3 Medical University of the Americas, Nevis, West Indies. 4 Universidad Iberoamericana (UNIBE), Santo Domingo, Dominican Republic. 5 Philadelphia College of Osteopathic Medicine, Georgia, Dept. of Biomedical Sciences, USA. 6 Memorial healthcare system, Pembroke Pines FL, USA. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 230-239 Publication history: Received on 23 September 2025; revised on 02 November 2025; accepted on 05 November 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.24.2.0985 Abstract Dedifferentiated parosteal osteosarcoma (D-POS) is an isolated form of osteosarcoma in which low-grade parosteal osteosarcoma (LG-POS) progresses into a high-grade sarcoma (HGS). In this case report, the clinical, radiological, pathological, and molecular evolution of D-POS in a 24-year-old male is described. The patient initially presented with a classic LG-POS of the proximal tibia, with amplification of MDM2 and CDK4, which was treated with a wide surgical resection and no neoadjuvant or adjuvant treatment. Three years later, he developed a progressively growing large mass with severe pain, and imaging appearance of a lytic tumor, necrosis, and medullary invasion at the site of prior surgery. The LG-POS had dedifferentiated into an HGS. The dedifferentiation of the LG-POS into high-grade sarcomatous component with severe atypia, high rate of mitosis, new mutations of TP53, and the amplification of MDM2 and CDK4 was found in histopathological examination of the recurrent mass. However, the patient died of progressive metastatic disease 2.5 years after the dedifferentiation despite the aggressive multimodal therapy, including neoadjuvant and adjuvant therapies, amputation, and pulmonary metastases metastasectomy. The case implies the highest importance of close follow-up and early detection of dedifferentiation, as well as the intricate nature of the prognosis of such aggressive variant of the tumor and necessity of developing standardized treatment plans. Keywords: Parosteal Osteosarcoma; Low-Grade; Dedifferentiation; High-Grade; Biphasic; Recurrence; Metastasis 1. Introduction Parosteal osteosarcoma (POS) is a rare low-grade sarcoma located on the surface of bones, which accounts for approximately 4–5% of total osteosarcoma cases. [1] POS occurs most frequently in the metaphysical area of long bones such as the distal femur and proximal tibia. [1] In most cases, POS is described as an asymptomatic, slowly growing mass over months to years and it has been shown to have a good clinical outcome with low metastatic potential when treated appropriately with surgical resection and negative margins. [2] It is histologically characterized by a well-formed osteoid in a spindle cell stroma and minimal cellular atypia. The low-grade morphologic features of POS lead to occasional misdiagnosed as a benign lesion. [3] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 230-239 231 POS can undergo dedifferentiation into a high-grade sarcoma. Dedifferentiation is the process when a tumor undergoes an aggressive transformation to a high-grade tumor. Dedifferentiation alters the behavior of the tumor, making recurrence or metastasis much more likely and leading to a significantly worse prognosis. [4] This transformation has been reported in 16% to 25% of POS cases, most commonly in recurrent or long-standing tumors. Early detection of this transformation is important for appropriate diagnosis and treatment [5] Histologically, HG-POS is characterized by a sharp transition from a low-grade component to an anaplastic, high-grade sarcomatous element. [6] The diagnosis of a Dedifferentiated Parosteal Osteosarcoma (D-POS) is often challenging, as the high-grade component can be focal, leading to misinterpretation on initial limited biopsy sample that may miss the high-grade component. [6] However, the use of advanced imaging changes, and testing for the MDM2 and CDK4 gene amplifications (a key feature of the precursor PO) in the high-grade component are crucial diagnostic clues. [7] The presence of dedifferentiation mandates an aggressive treatment regimen, including systemic chemotherapy, which is typically not required for conventional LG-POS. [8] This case report illustrates the clinical, pathological, and molecular profiles of a rare case of a 24-year-old-man who presented with low-grade surface parosteal osteosarcoma (LG-POS) that later dedifferentiated to a high-grade parosteal osteosarcoma (HG-POS). We highlight the importance of long term follow up in such patients and the need for a meticulous diagnostic workup, including advanced molecular studies to confirm dedifferentiation. Our case illustrates the dismal prognosis and the aggressiveness of this transformation, lending significance to the sparse literature on this rare condition. 2. Case presentation 2.1. Clinical presentation A 24-year-old healthy male presented to the hospital with a 6 months history of progressive and dull aching pain in the right knee area. The pain initially was intermittent, but with continued use, it became constant and no longer activityrelated. He was complaining of progressive swelling and reported that he had a firm, non-mobile mass at the right knee, which had been gradually increasing over a period of 4 months. The patient did not have any previous trauma, fever, weight loss, or night sweats, and no family history of bone tumors or genetic syndromes. Physical examination showed a large, hard, fixed mass of about 8 cm in diameter at the medial aspect of the right knee. The skin covering was normal, with no erythema or warmth. Knee pain and a mass effect limited the range of motion, with flexion restricted to 90 degrees. Neurovascular examination was intact but limited to the distal extremities. 2.2. Preliminary imaging diagnosis and differential diagnosis Radiographs of the right knee showed a large, lobular, and densely mineralized mass on the medial cortex of the proximal tibial metaphysis with the characteristic appearance of cauliflower-like parosteal osteosarcoma. The mass showed peripheral and septal calcification, with a radiolucent center. It had no cortical breakthrough or medullary involvement, and the mass appeared to protrude from the outer cortex of the bone. (Figure 1) On T1-weighted images, MRI revealed an 8.5 x 6.0 x 7.2 cm heterogeneous mass with low to intermediate signal intensity, and mixed signal intensity on T2-weighted sequences, representing the mineralized matrix. Mass attachment to the medial tibial cortex was broad-based, and there was extensive extension of the mass towards the soft tissue without invasion of the tibial cortex or the medullary cavity. A CT scan confirmed the pattern of mineralization. Surface parosteal osteosarcoma, surface periosteal osteosarcoma, osteochondroma with malignant transformation, and myositis ossificans were included in the differential diagnosis. Table 1 summarizes the key differential diagnoses of LG-POS. 2.3. Pathology and confirmatory studies A core needle biopsy of the mass gave typical results of low-grade parosteal osteosarcoma (LG-POS). Histologically, the tumor consisted of well-differentiated fibroblastic spindle cells arranged in fascicles, embedded in abundant osteoid and woven bone matrix. Atypia was limited, and mitoses in the spindle cells were rare (1-2 in 10 high-power fields). The osteoid was complete and had a basket-weave mark, which is typical of parosteal osteosarcoma. The proliferation index, as measured by Ki-67, was relatively low, with approximately 8% nuclear staining. Immunohistochemistry (IHC) studies supported the diagnosis of LG-POS. The FISH amplification of MDM2 was positive, confirming the diagnosis and ruling out a reactive bone-forming lesion. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 230-239 232 2.4. Treatment of initial low-grade parosteal osteosarcoma No neoadjuvant therapy was provided, and the patient had undergone a wide surgical resection with a negative margin attained. Given the low grade and negative margins, no adjuvant chemotherapy was administered. However, due to focal areas of margin involvement noted on the final pathology report, adjuvant radiation therapy (60 Gy in 30 fractions) was administered to the surgical bed and surrounding tissues. The recovery phase was uncomplicated, and the patient returned to modified work duties after 3 months. 2.5. Recurrence and clinical deterioration Three years later, the patient presented to the orthopedic service with a 4-month history of a mass at the same site that had rapidly increased in size. He complained of acute, chronic pain that needed narcotics, and night pain that disturbed his sleep. The mass had increased to approximately 12 cm, becoming hard and fixed, with irregular boundaries. Plain films revealed an aggressive, 12 cm, irregularly infiltrating, mixed lytic and sclerotic mass, with marked extension into the surrounding soft tissue. CT studies revealed a broad-based, ossified mass on the bone's surface, associated with a large soft-tissue component, with invasion of the cortex and the medullary cavity; MRI revealed irregular signal intensity. Differential diagnosis included D-POS, secondary high-grade osteosarcoma, other high-grade sarcomas (such as pleomorphic sarcoma and leiomyosarcoma), and metastatic disease. 2.6. Pathology of recurrent tumor (dedifferentiation): The histomorphology of the biopsy of the recurrent mass was indicative of a D-POS (Dedifferentiated Parosteal Osteosarcoma) of striking biphasic features. The predominant morphologic component was high-grade sarcomatous regions, admixed with smaller areas of LG-POS, as in the original tumor. The high-grade component consisted of highly pleomorphic spindle and giant cells with severe nuclear atypia and abundant abnormal mitotic figures (>30 mitoses per 10 HPF). The tumor exhibited low levels of osteoid production, compared to the well-differentiated, low-grade regions. (Figure 2 A, B, C, D) IHC studies on the high-grade component demonstrated a positive result for CD68 (osteoblastic giant cells), vimentin, CD99, and smooth muscle actin in both the pleomorphic and the spindle cell components. S-100, desmin, myogenin, myoid-1, CD31, CD34, pan melanocytic markers, and cytokeratins were negative. (Figure 3 A, B, C, D, E) High-grade MDM2 IHC-positive results indicated that the recurrent tumor was related to the initial low-grade tumor. The high-grade component had a significantly high Ki-67 proliferation index of 60-70%, whereas the residual low-grade component had a low index of less than 10%. In both components, molecular studies confirmed the amplification of MDM2 and CDK4. Further genetic studies identified new TP53 mutations and amplified chromosomal instability in areas of high-grade disease, consistent with the process of dedifferentiation. 2.7. Treatment of recurrent dedifferentiated parosteal osteosarcoma The diagnosis was D-POS with transformation to high-grade surface osteosarcoma. The patient has been put on an advanced treatment regimen for osteosarcoma. During the 12 weeks, he received four cycles of the MAP (methotrexate, adriamycin, cisplatin) regimen as neoadjuvant chemotherapy. The imaging performed post-neoadjuvant showed a partial response, with tumor size decreased by 30%. The multidisciplinary tumor board recommended above-knee amputation as the best intervention to undertake instead of limb salvage surgery to achieve sufficient margins and optimal local control. The patient had been amputated (above the knee) and had received adjuvant chemotherapy. 2.8. Metastasis and outcome: Follow-up with CT chest at 18 months revealed four bilateral pulmonary nodules, the largest measuring 2.5 cm; biopsy of one of the nodules confirmed metastatic osteosarcoma. Bilateral thoracotomy was performed, and the four nodules of the pulmonary metastasis were completely excised and recovered successfully. He was placed on second-line chemotherapy using ifosfamide and etoposide for six cycles. Although he was treated aggressively, the patient developed new pulmonary metastases 8 months after thoracotomy. He had been put on a clinical trial of novel targeted therapies against MDM2-amplified sarcomas. Unfortunately, he died 2.5 years following dedifferentiation discovery due to progressive metastatic disease. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 230-239 233 Figure 1 CT findings of the initial low-grade surface parosteal osteosarcoma There is a broad-based, ossified mass on the bone's surface associated with a large soft tissue component without invasion of the cortex or medullary cavity (red arrow). 1A: Low power view showing infiltrating solid and myxoid tumor morphology (H&E stain X20); 1B: High power view showing pleomorphic sarcomatous tumor cells with abundant abnormal mitosis (5 mitosis in a single field, blue arrows) (H&E stain X60); 1C: High power view showing spindle cell sarcomatous cells with increased abnormal mitosis (blue arrows) (H&E stain X60); 1D: High power view showing malignant sarcomatous cells forming malignant osteoid (H&E stain X40) Figure 2 Histomorphology of the high-grade dedifferentiated surface parosteal osteosarcoma World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 230-239 234 1A: Tumor cells positive for vimentin; 1B: Tumor cells positive for CD99; 1C: Tumor cells positive for smooth muscle actin; 1D: Tumor cells negative nuclear staining of Myoid-1 (cytoplasmic staining is not considered positive); 1E: Tumor cells negative for cytokeratin 5.2 Figure 3 Immunohistochemistry of the high-grade dedifferentiated surface parosteal osteosarcoma Table 1 Key differential diagnosis of low-grade parosteal osteosarcoma (LG-POS) Feature Low-Grade Parosteal Osteosarcoma (LGPOS) Osteochondroma Myositis Ossificans (Mature Stage) Low-Grade Central Osteosarcoma Clinical Painless, slow-growing mass (years). Peak in 3rd-4th decade. May restrict joint movement (e.g., knee flexion). Painless, fixed mass. Usually in adolescents/young adults. History of trauma/inflammation (weeks-months). Painful early, then fixed/painless. Located in adjacent soft tissue/muscle. Pain, swelling. Located centrally/intramedullary. Similar age to LGPOS. Radiology Dense, lobulated, broad-based mass on the cortical surface (metaphysis/proximal tibia). Lucent cleft/line ("string sign") between tumor and cortex often seen. Minimal to no medullary invasion. Cortical and medullary continuity with the host bone. Exostosis with a visible cartilage cap (MRI). Extraskeletal mass, separate from the cortex. Zonal phenomenon: Denser/more mature ossification at the periphery (rim) and less dense centrally. Intramedullary (central), ill-defined sclerotic or mixed lesion. Permeative growth into the cortex. Microscopic Hypocellular spindle cell stroma with minimal atypia. Production of wellformed, irregular, or parallel bony trabeculae. May show invasion of adjacent soft tissue/muscle. Benign cartilage cap (hyaline cartilage) over an underlying bony stalk. Continuous cortical and medullary bone beneath the cap. Zonal arrangement (reverse of LGPOS): Immature cellular tissue centrally with progressively maturing bone/ossification peripherally. Atypical spindle cells in a low-grade background. Irregular, haphazardly arranged bony trabeculae (woven bone). Permeative border with normal marrow/bone. IHC Generally Nonspecific. Cells are Vimentin (+), often SATB2 (+). Used to exclude other entities (e.g., S100 for chondrosarcoma). Chondrocytes in the cap are S100positive. Nonspecific, generally not required for diagnosis. Nonspecific. Usually SATB2-positive. Molecular Characteristic: Supernumerary ring chromosomes containing MDM2 and CDK4 gene Inactivation of the EXT1 or EXT2 genes (especially in hereditary cases). Primarily a reactive process. No consistent, recurrent, specific chromosomal or gene aberrations. Shares MDM2 and CDK4 gene amplification (detected by FISH) with LGPOS, but is centrally located. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 230-239 235 amplification (detected by FISH). *Complied from References 3, 5, 7, 8, 13, 14.19 3. Discussion 3.1. Background (History, epidemiology, risk factors, and WHO classification) In 1951, POS was first described as a low-grade, slow-growing, rare malignant bone tumor that occurs at the outermost layer of bone periosteum. It was described as a variant of osteosarcoma representing approximately 4-5 percent of all osteosarcomas and is the most prevalent form of surface (juxtacortical) osteosarcoma. [9] On an epidemiologic scale, POS is slightly female-predominant and typically presenting in the third decade of life, some 10-15 years earlier than the typical presentation of conventional osteosarcoma. [10] Long bones metaphysis is the most common tumor location with approximately 70-80 percent of the cases being described at the posterior side of the distal femur. They most frequently occur in the proximal tibia and humerus. [9] [10] The etiology of parosteal osteosarcoma is unclear. Nevertheless, a history of radiation therapy, Paget’s disease of bone and prior bone trauma are some of the identified risk factors. [9] Genetic predisposition is also suggested because some hereditary disorders, including Li-Fraumeni syndrome and TP53 gene mutations have been associated with increased risk. [11]. In WHO 5th edition of the classification of bone tumors, surface osteosarcomas of the bone are grouped into 3 categories: parosteal osteosarcoma, periosteal osteosarcoma, and high-grade surface osteosarcoma. The best differentiated and low-grade type in this spectrum is parosteal osteosarcoma. The possibility of dedifferentiation, or the development of a low-grade tumor into a high-grade sarcoma, is one of the notable characteristics of its natural history. Such conversion, which is seen in 15-43 per cent, can be present at the time of first presentation (synchronous) or more commonly at the time of recurrence (metachronous). [12] [13] 3.2. Pathogenesis and Pathophysiology Specific genetic alterations characterize the pathogenesis of LG-POS. Cytogenetically, these tumors are characterized by the presence of supernumerary ring chromosomes which amplify material of the chromosomal region of 12q13-q15. This amplification results in the overexpression of MDM2 and CDK4 genes that are present in more than 85 percent of the cases. Such genes are essential controlling factors of the cell cycle, and their amplification is a key molecular signature that helps distinguish parosteal osteosarcoma from other benign bone-forming lesions. [14] [15] Dedifferentiation or acquisition of high-grade features of sarcoma, is a major change in the tumor biology. Although the dedifferentiated component tends to have the typical MDM2 and CDK4 amplification of the initial low-grade tumor, it develops other genetic mutations. New mutations, such as TP53, and chromosomal instability are frequent in the highgrade areas as observed in the case presented. [14] It is a genetic development that results in a more aggressive tumor, with the characteristics of an osteosarcoma of high grade, undifferentiated pleomorphic sarcoma, or another high-grade sarcoma. [12] The high-grade component is linked to a higher mitotic rate, cellular atypia, and higher propensity to metastasis. [8] This progression to an aggressive, high-grade malignancy in place of a slow-growing and low-grade tumor is a critical step, which severely deteriorates the prognosis of the patient and requires an approach to treatment that is more aggressive in nature. [8] [12] 3.3. Comparative analysis of our case with the existing literature 3.3.1. Clinical presentation and radiology The initial history of our patient—dull ache in the knee slowly progressing over a period of six months, then associated with swelling and development of a firm fixed mass, closely resembles the usual presentation of parosteal osteosarcoma as described in many series. As reported, patients usually present in the second to fourth decades of life with an indolent pain and slowly enlarging surface mass; frank systemic symptoms are rarely seen. [10] [12] The lack of constitutional symptoms in our case is also consistent with the benign clinical course of LG-POS. [16] The transition observed in our patient, however, to a more aggressive clinical syndrome paired with unremitting intense pain (including pain during sleep) and rapid lesion enlargement, parallels the progression described in cases of D-POS, which were also related to an initial lag period followed by progression to a more malignant phenotype. [17] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 230-239 236 On radiographs, the initial lesion in our case revealed a densely ossified lobulated broad-based mass which appeared to arise from the cortex with a “cauliflower” appearance and no obvious central involvement—typical of POS. [18] As described, POS lesions are frequently well-ossified tumors with a lucent cleavage plane/interface to cortex and either no cortical destruction or minimal destruction. [19] MR characteristics of low-grade lesions usually have low signal on T1and T2-weighted imaging (because of the densely mineralized component) and have relatively well-demarcated margins. [3] [9] In our case, both MRI and CT supported a mineralized lesion and excluded medullary involvement, allowing the differentiation from other surface lesions such as osteochondroma or myositis ossificans [10] [18] Our case developed into a large (≈12 cm), mixed lytic–sclerotic lesion with ill-defined borders, soft tissue extension, necrosis, and medullary canal invasion on MRI/CT. Imaging change in appearance on imaging has also been welldocumented in the D-POS literature: radiographic progression toward nonuniform ossification, cortical eruption, and extension into surrounding soft tissues are a red flag for dedifferentiation. [6] [12] Published series including Bertoni et al., reported internal lucent areas in prior sclerotic lesions in numerous cases of D-POS and invasion of the medullary canal in approximately 65% of dedifferentiated tumors. [12] There have also been reports of MRI findings in POS possibly being related to dedifferentiation, such as high or heterogeneous T2 signal intensity (often secondary to necrosis/hemorrhage) and ill-defined margins; nevertheless, sonographic and MR signal alone are not reliable enough for determining malignancy. [17] In our case, the findings of necrotic foci, heterogeneous signal, and marrow infiltration closely resembled those reported for dedifferentiated lesions. [17] [19] In general, our patient’s progression—low-grade prototypical parosteal osteosarcoma to a high-grade, radiographically aggressive lesion—is very parallel to the natural history and imaging evolution seen in DPOS series. The clinical and radiologic change emphasizes the need for close long-term imaging follow-up and a high index of suspicion for dedifferentiation in patients with a history of parosteal osteosarcoma. 3.3.2. Diagnosis (Laboratory tests, pathology, IHC, and molecular findings): A core needle biopsy was made in the initial diagnosis of LG-POS and the histological features showed the same features as described in the literature. The biopsy demonstrated that there were well-differentiated fibroblastic spindle cells in fascicles within a rich osteoid and woven bone with minimal cytologic and atypia and low mitotic rate (1-2 mitoses in 10 high-power fields). [9] [14] A histological feature of POS is the presence of fully developed osteoid having a basketweave pattern. The low-grade nature of the tumor was also supported by the low index of Ki 6 7 proliferation (around 8% nuclear staining). The IHC investigations and positive FISH amplification of MDM2 played a vital role in making the diagnosis and distinguishing it from reactive bone-forming lesions, which is in line with the standard diagnostic requirements. [9] [14] [15] The dedifferentiation was strongly supported by the histomorphism of the recurrent mass. The biopsy showed dramatic biphasic aspects with greater high-grade sarcomatous foci and smaller ones of low grade parosteal osteosarcoma both being a replica of the original tumor. The high-grade constituent was highly pleomorphic spindle and giant cells, severe nuclear atypia, and rich abnormal mitotic figures (>30 mitoses per 10 HPF), which were compatible with the dedifferentiated lesion aggressiveness. [10] [19] This poorly differentiated component was much lower in osteoid production than the well differentiated areas. The high-grade component of the tumor showed positive result of CD68, vimentin, CD99, and smooth muscle actin in IHC studies, and negative result of S-100, desmin, myogenin, myoid-1, CD31, CD34, and pan melanocytic markers. Importantly, the high-grade component was IHC-positive for MDM2, which indicated that it is related to the original low-grade tumor lineage. The index indicator of Ki-67 proliferation in the high-grade element was significantly higher (60-70%), as compared to the residual low-grade element (<10%), which is a characteristic of dedifferentiation and enhanced proliferative action. [12] [15] The amplification of both components regarding MDM2 and CDK4 was confirmed through molecular study, which strengthened the diagnosis. In addition to this, the dedifferentiation process was supported by the molecular basis of the new TP53 mutations and amplified chromosomal instability that is identified in the high-grade areas, which is in line with the literature regarding the evolution of genes in aggressive sarcomas. [6] [12] The case shows that there is a clear pathological and molecular evolution of LG-POS to D-POS with specific histological alterations, elevated proliferative rate, and emergence of other genetic deviations. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 230-239 237 3.3.3. Management and outcomes The management of the low-grade parosteal osteosarcoma in the patient included wide negative margin resection initially. This is in line with the general management of low grade parosteal osteosarcoma in which surgical excision is the major and, in most cases, curative modality of treatment. [2] [11] The grade and negative margins made adjuvant chemotherapy unnecessary and this has been in line with the present guidelines regarding well-differentiated parosteal osteosarcomas. Nonetheless, since the pathology report indicated focal involvement of the surgical margins by tumor, adjuvant radiation therapy (60 Gy in 30 fractions) was done to the surgical bed. Although it is not always applicable to all cases of low-grade parosteal osteosarcomas, adjuvant radiations may be adopted when the margins are close or focally positive to avert chances of local relapse. [2] [8] [18] The spontaneous recovery and resumption of the patient into modified work activities in 3 months indicates a good first response, which is characteristic of a good response to the treatment of low grade parosteal osteosarcoma. After the diagnosis of D-POS, the management strategy largely intensified. This patient was put on to a more advanced treatment plan of the osteosarcoma starting with the neoadjuvant chemotherapy using a four-cycle of the MAP (methotrexate, adriamycin, cisplatin) regimen in 12 weeks’ time. This is an aggressive chemotherapy regimen typically used to treat high-grade osteosarcomas, such as dedifferentiated ones, and to treat systemic disease and enhance resectability. [8] The partial response which was noted after the neoadjuvant imaging (30 percent shrinkage in the tumor size) showed that there was a certain degree of efficacy of the chemotherapy. Although the response was partial, the recommendation of the multidisciplinary team was above-knee amputation rather than limb salvage surgery to be able to attain a sufficient margin and the most local control possible. This observation highlights how aggressive dedifferentiated lesions are and how important total tumor resection, even at the expense of limb sparing, is, particularly when clear margins are challenging with limb-sparing procedures. [3] The patient was successfully amputated and got adjuvant chemotherapy and this once again highlights the high-grade character of the disease and the systemic treatment required to overcome the possibility of recurrence and metastases. Regrettably, the patient developed bilateral pulmonary metastases 18 months after being amputated, which is a frequent location of the metastases of osteosarcoma. Biopsy was metastatic osteosarcoma and bilateral thoracotomy was performed with metastasectomy of the four nodules in his lungs. Pulmonary metastases that are surgically excised are a known way of enhancing survival in the selected osteosarcoma patients. [2] New pulmonary metastases occurred 8 months following thoracotomy despite being treated aggressively, which was a sign of a refractory disease. Subsequently, the patient was admitted to a clinical trial of new targeted therapies to MDM2-amplified sarcomas, which is an indication of the efforts to find alternative therapies in the case of advanced and resistant cases. Unfortunately, the patient died of the progressive metastatic illness 2.5 years following the dedifferentiation identification. This is a tragic result, but it illustrates that the prognosis of D-POS, in contrast to that of its low-grade counterpart, is poorer with high probabilities of local recurrence and distant metastasis regardless of aggressive multimodal treatment. [11] [12] 3.4. What have we learned from this case? The dedifferentiated parosteal osteosarcoma presented in this case provides the medical fraternity with some very important lessons. It is essential that patients who were initially diagnosed with LG-POS should be vigorously observed with a long-term follow-up in the first place. Even after complete surgical resection with negative margins, dedifferentiation and subsequent aggressive recurrence is also of great concern. This is because the rapid clinical evolution, which is more painful and gives rise to a rapid growth of a mass, should immediately indicate the possibility of malignant transformation in which a more serious re-evaluation should be conducted with the help of more sophisticated imaging and biopsy. Secondly, the case emphasizes the drastic change of radiological and pathological characteristics in case of dedifferentiation. The progression of a clearly defined, densely mineralized mass into aggressive lesion with lytic and sclerotic foci, necrosis and medullary invasion on radiographic features is a significant predictor. Molecular signature of dedifferentiation is well manifested pathologically by the development of a high-grade sarcomatous component with severe atypia, high mitotic activity, and high index of Ki-67, and the preservation of MDM2 and CDK4 amplification and the development of new TP53 mutations. This highlights the importance of extensive pathological and molecular studies of recurrent lesions to offer proper treatment. Lastly, the case demonstrates D-POS, which is aggressive and difficult to manage. Although the patient was subjected to aggressive multimodal therapy which involved neoadjuvant, adjuvant chemotherapy, amputation and metastasectomy, the patient eventually succumbed to progressive metastatic disease. The result supports the idea that D-POS acts like World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 230-239 238 conventional high-grade osteosarcoma and requires aggressive treatment plans and requires the development of new therapeutic options, especially in cases of MDM2-amplified sarcomas, as demonstrated by the inclusion of the patient in a clinical trial. Abbreviations • Parosteal osteosarcoma (POS); • Dedifferentiated parosteal osteosarcoma (D-POS); • low-grade parosteal osteosarcoma (LG-POS); • High-grade parosteal osteosarcoma (HG-POS); • High-grade sarcoma (HGS); Immunohistochemistry (IHC) 4. Conclusion The case report of dedifferentiated LG-POS to a high-grade osteosarcoma serves as a heartbreaking illustration of the malignant character that even initially low-grade bone malignancies may possess. Our measurement of clinical, radiological, pathological, and molecular development of this rare case, outlining it in finer detail, will become the valuable contribution to the existing medical literature. The report highlights the strong necessity to identify the symptoms of dedifferentiation that requires a radical change in the approaches to diagnosis and treatment. The importance of reporting such cases is to increase awareness of clinicians, pathologists, and radiologists on the natural history and problematic treatment of D-POS. Moreover, it reveals the essentiality of the further investigation of specific treatments of the aggressive MDM2-amplified sarcomas, eventually attempting to alleviate patient outcomes in the context of the such potent disease. Compliance with ethical standards Acknowledgments Special thanks to Sandhia Senthilnathan, Melissa Perez for their assistance in reviewing the final manuscript. Additionally, we appreciate the assistance of Grammarly's language editor, which provided valuable writing support by identifying and correcting errors in grammar, spelling, punctuation, and style, ultimately enhancing the manuscript. Disclosure of conflict of interest All authors make the following declarations: • Payment/services information: All authors have declared that they received no financial support from any organization for the submitted work. • Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might be interested in the submitted work. Statement of ethical approval Ethical review and approval were not required for this study involving human participants. The paper has been sufficiently anonymized to maintain the patient's confidentiality. Data access statement All relevant data are included in the paper. Author contributions All authors contributed equally to producing this manuscript. Statement of informed consent The patient expired, and all attempts to reach the family members were unsuccessful. Therefore, the paper has been sufficiently anonymized to maintain patient confidentiality.