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Meta-analysis of 65 Adamantinoma case reports: Unveiling symptomatology, demographics, and treatment outcomes in contrast to prior understandings
⁎Corresponding author: Vijay Patel. vp540@mynsu.nova.edu
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Received: ,
Accepted: ,
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Abstract
Adamantinomas are rare, malignant bone tumors predominantly affecting the tibia. This study compares demographics, clinical presentations, radiographic findings, metastasis rates, and treatment outcomes of adamantinoma cases from a contemporary review of 65 cases with a historical review by Keeney et al. (1989). Our data reveals a significant increase in the average age at diagnosis, from 25.9 years in the prior study to 38.1 years in the new study, with notable increases for both males and females. The metastasis rate in our study was 45.3 %, significantly higher than the 23.5 % reported previously with a wider range of possible sites. Treatment options have changed with significant improvement in survivability and remission with allograft and endoprosthesis techniques compared to older techniques of amputation and resection. This study highlights the evolving understanding of adamantinoma, emphasizing the changes in presentation and the effectiveness of advanced surgical treatments.
1 Introduction
Adamantinomas are rare malignant bone tumors which commonly arise on either the epiphysis or anterior diaphysis of the tibia. These tumors are often recurring and metastasize to the lungs, making a timely diagnosis crucial. Current data suggests a metastasis rate of 12–29 %.1 There are two main types of Adamantinoma: The classic type presents in the 4th decade of life with further differentiation based on histology and the differentiated type in the second decade. Current data suggests there is a slight predominance in males.2,3 Diagnosing an adamantinoma can prove difficult due to the equivocal presentation. Most notably, initial symptoms are related to pain at night and vague leg pain.4 These initial symptoms are commonly excused as normal growing pains.4 Due to the vagueness of symptomology and high risk for metastasis, a strong clinical suspicion is vital to begin further evaluation. Therefore, imaging studies are crucial to diagnosing an adamantinoma. Plain radiographs are primarily used to diagnose an adamantinoma and will show a lytic soap bubble lesion.5 This alone may not lead to a diagnosis since lytic lesions are a common presentation of other conditions such as giant cell tumors and osteofibrous dysplasia. Thus histological evaluation is often necessary to further distinguish an adamantinoma from other lesions.6 However, there are a wide array of histological presentations of Adamantinoma.
2 Histology
Histologically there are 4 types of classic Adamantinoma: basaloid, tubular, spindle-cell and squamous.2 Additionally there is a subtype coined osteofibrosis dysplasia like adamantinoma which consists of benign osteofibrous tissue containing malignant cells.6 Each type of Adamantinoma sub-type is named corresponding to the predominant cell type. Basaloid contains nests of basaloid cells which are arranged in peripheral palisading.7 The tubular sub-type is made of a line of cuboidal cells with central discohesion.7 The spindle type displays cellular spindling which can be differentiated from other cancers because of a lack of carcinoma characteristics that will be discussed in the immunohistochemistry section. Similarly, the squamous type may appear like a squamous carcinoma, but also lacks carcinoma characteristics which helps with differentiating the diagnosis.2 In contrast to their epithelial cell types, osteofibrous dysplasia like Adamantinoma shows “bland spindle cells with irregular trabeculae of woven bone” which also has a much more benign course.6
3 Immunohistochemistry
Specific stains are crucial and must be considered. Typically, these tumors exhibit positive staining for keratin AE1 and AE3. AE1 detects high molecular weight cytokeratins 10, 14, 15, and 16, alongside low molecular weight cytokeratin 19, while AE3 identifies high molecular weight cytokeratins 1–6 and low molecular weight cytokeratins 7 and 8. In adamantinoma cytokeratins 5, 14, and 19 are typically positive8 while negative cytokeratin 8 and 18 staining is typically seen.7 Cytokeratins are integral to cytoskeletal intermediate filaments and are predominantly expressed in epithelial tissues, thereby highlighting immunoreactivity in epithelial-derived tumors. Vimentin is also positive, demonstrating a mesenchymal origin.
4 Methods
The National Center for Biotechnology Information (NCBI) was searched on October 29th, 2023 with the key words “Adamantinoma”, “Case report”, and “case study”. This yielded 448 articles. An initial screen was done to remove articles that were irrelevant, non-english text, abstracts, and duplications. A final selection was made of 65 articles to review. Each article was independently screened for objective information such as patient demographics: age and sex, clinical information: chief complaint, tumor size, imaging findings, treatment plan, and patient outcomes as well as treatment outcomes, metastasis, tumor recurrence, and treatment complications.
5 Results
Of the 65 cases reviewed 27 patients were female, 31 were male, and 7 cases did not report the sex. The average age of the patient at diagnosis was 38.1 years old with men being 35.2 years old and women being 40.3, however the range was from 3 months to 76 years giving a wide distribution of possible ages (see Fig. 1).
54 cases found the initial tumor on the appendicular skeleton while 6 cases were found on the axial skeleton. In 4 cases the tumor moved from the appendicular to the axial skeleton and 2 of those cases specifically spread to the spine. The tumor was found in the tibia in 45 cases (including the tibia and fibula in 1 case), the femur 6 cases, the mandible in 3 cases, and the fibula in 2 cases. Other locations included the pelvis, calcaneal, humerus, vertebra, T11/T12 vertebral bodies, right 7th rib, and tibia to lymph nodes, each in 1 case. This data highlights a predominant occurrence of tumors in the tibia with a capacity to originate in other sites.●Clinical presentation
Anterior leg pain was found in 12 cases. This pain was described as dull, intermittent, achy, and often intensified at night. In one unique case, the anterior leg pain progressed to numbness and eventual motor weakness. Swelling over the area of the tumor was documented as the first symptom in 8 cases. The swelling, most often over the tibia, was commonly described as painless. Pathological fractures were documented as the presenting symptom in 10 cases. Fractures as the initial symptom were most common in advanced cases, where the bone had become weakened, increasing the likelihood of a fracture. Other, less common, presenting symptoms include palpable masses, usually on the anterior aspect of the tibia and were associated with extreme tenderness, and skin changes such as erythematous and tropic change. Symptomatology was associated with tumor location. Of the 65 total cases, our research found a wide array of non-specific symptoms, which is why early imaging studies are crucial to achieving a timely diagnosis.●Radiographic findings
There are more instances where tumors did not have an associated fracture (39 cases) compared to those that did (13 cases). This includes one unique case where the tumor metastasized to the spine and resulted in a fracture. The radiographic findings in the cases exhibit a variety of osteolytic lesions, primarily affecting the tibia but also involving other skeletal sites such as the fibula, mandible, and vertebral bodies, with lesions ranging from simple lytic lesions to more complex descriptions such as finely trabeculated, osteolytic lesions with well-defined margins, and multi-lobulated osteolytic lesions with a “moth-eaten” appearance. Some lesions are described as well-circumscribed with mixed sclerotic and lytic characteristics, indicating a combination of bone destruction and formation. These descriptions suggest the presence of aggressive bone pathology with potential malignancy.
The findings also indicate several cases of pathological fractures, which are fractures that occur in bones weakened by disease. Examples include a lytic lesion with septation at the midshaft of the tibia without periosteal reaction and another involving multiple patchy cortical erosions and irregularities. Notably, one case mentions a lytic expansile lesion with multiple septa and sclerotic margins involving the tibia's diaphysis, while another highlights a multi-lobulated osteolytic lesion in the middle shaft of the tibia with a “moth-eaten” appearance.
In addition to tibial involvement, the findings mention lytic lesions in the fibula, mandible, and vertebral bodies. For instance, the description of a multilocular osteolytic lesion in the distal fibula with cortical thinning and an osteolytic mass extending from the second left premolar to the condylar neck highlights the spread and severity of these lesions. The vertebral body lesions demonstrate destructive changes and mixed lytic/sclerotic appearances, often with soft tissue masses and pathological fractures. MRI findings of the thoracic spine reveal vertebral body destruction from T1-T4 with pathological fracture of the T2 vertebral body and mixed lytic/sclerotic appearance on CT, reflecting the complexity and extent of bone involvement●Rate of metastasis
Out of 65 cases, 29 cases reported metastasis. The lungs are the most frequently affected site, with a total of 13 cases showing metastasis solely to the lungs, including instances where the lungs are involved along with other sites. The spine is another significant site for metastasis, with a total of 7 cases, including 4 cases where only the spine is affected and additional cases where the spine is involved along with other sites.
Several cases showed multiple sites of metastasis including 1 case of metastasis to both the lungs and lumbar spine, and 1 case involving both the femur and lungs. The inguinal lymph nodes are affected in 2 cases, one of which also involves the lungs. Additionally, there is 1 case of metastasis to the right lung and 6th to 8th ribs, and another involving both the lungs and large pelvic nodes. Other metastasis sites include the breast (1 case of breast carcinoma), prostate (1 case metastasized from the prostate), L1 vertebrae (1 case), liver (1 case), pancreas (1 case), and skull (1 case).●Treatment plan
Surgery is the mainstay of treatment. There were 12 cases of general resection, including 1 en bloc resection and reconstruction, 1 resection with contralateral fibular osteoadiposal flap, and 1 radical resection with allograft reconstruction. Tumor resection and osseous graft reconstruction were performed in 2 cases. Amputation was performed in 7 cases. Additionally, there were 2 cases where resection was followed by below the knee amputation seven years later.
Other significant treatments included allografts in 7 cases, with specific procedures involving allograft-prosthetic, allograft and lymph node (LN) dissection, surgical resection and allograft, and total resection with allograft reconstruction. Curettage and bone grafting were common, with 3 cases of curettage and bone grafting, 1 case of curettage and cementing, and various surgical excisions combined with curettage and bone grafting. Notably, there were specialized surgeries such as free fibula flap (1 case), fibulectomy (1 case), mandibulectomy (1 case), corpectomy (1 case), and inguinal lymphadenectomy (1 case). The treatment data also includes instances of patients refusing surgery (1 case) and not specifying their treatment (3 cases).●Treatment outcomes
We divided treatment outcomes into “positive” and “negative” outcomes. 61 cases reported positive outcomes which included key words such as cured, full recovery, remission, and survived while negative outcomes included recurrence, death, and metastasis. There were 24 negative outcomes and 34 positive outcomes with a calculated P-value of 0.456 with an alpha of 0.05 thus we were not able to determine a statistical significance between positive and negative outcomes. Specific follow-up periods showed the following remissions: 2 cases at 3 months, 1 case at 6 months, 2 cases at 2 years, 2 cases at 3 years, 2 cases at 5 years, 1 case at 9 years, and 7 cases with 15 years of follow-up.
Recurrences were observed at various intervals: within 1 year in 3 cases, at 1.5 years in 1 case, at 2 years in 1 case, at 3 years in 2 cases, at 3.5 years in 1 case, at 5 years in 2 cases, at 6 years in 2 cases, at 6.5 years in 1 case, at 7 years in 2 cases, and at 25 years in 1 case. There was also 1 case with 6 recurrences over 15 years.
Metastasis to the spine occurred in 4 cases, and there was 1 case where the tumor spread to the lungs. There were 3 cases of death: 1 case 17 months later, and 2 cases secondary to lung metastases, including one that occurred 3 months later. 4 cases where the outcome was either not specified or not stated. One of these patients had refused surgery and no follow-up was performed.
6 Specific treatment success rates
In our study, resection procedures showed a success rate of 53.6 %, with 15 out of 28 cases resulting in positive outcomes such as cured status, full recovery, primary tumor removal, and remission. However, 13 cases experienced failure, indicated by metastasis, recurrence, or relapse. Curettage procedures demonstrated a slightly higher success rate at 62.5 %, with 5 out of 8 cases resulting in remission or cure, while 3 cases experienced recurrence. Amputation had the lowest success rate among the main treatment types, with only 6 out of 14 cases (42.9 %) resulting in remission or survival, and a high failure rate of 57.1 %, including deaths and recurrences.
Allograft procedures were the most successful, with all 11 cases resulting in remission, reflecting a 100 % success rate. Similarly, endoprosthesis treatment showed a 100 % success rate, although only 2 cases were reported. Among the miscellaneous treatments, individual procedures such as surgical excision with curettage and bone graft, resection of rib and hepatic tumor, tumorectomy with spondylectomy, and metastasectomy with cementation each had a 100 % success rate in their respective single cases. Conversely, excision with curettage and supervoltage X-ray had a 100 % failure rate, and one bone graft case had an unknown outcome
7 Discussion
In 1989 Keeny et al. reviewed 85 cases of adamantinoma to analyze clinical and demographic data. We will compare the results from this previous study to ours to observe any changes over time.
7.1 Age
The comparison between the prior study and the new study reveals significant changes in the average ages at diagnosis over time. The overall average age at diagnosis in the prior study was 25.9 years,9 while the new study reported an average age of 38.08 years. This difference is statistically significant with a t-value of 5.66 and a p-value of 7.43 × 10−8, indicating a notable increase in the age at diagnosis over time. When examining the male patients, the prior study reported an average age of 27 years,9 compared to 35.2 years in the new study. This difference is also statistically significant, with a t-value of 3.81 and a p-value of 0.000205, showing a significant increase in the age at diagnosis for male patients. Similarly, for female patients, the average age at diagnosis in the prior study was 24 years,9 whereas in the new study, it increased to 40.3 years. This change is statistically significant, with a t-value of 7.57 and a p-value of 3.72 × 10−12, highlighting a substantial rise in the age at diagnosis for female patients. Overall, these findings indicate significant shifts in the demographic characteristics of the patient population over time, with patients being diagnosed at older ages in the new study compared to the prior study.
7.2 Metastasis
The comparison between our study and the prior study reveals significant differences in metastasis patterns and rates. In our study, metastasis was reported in 29 out of 64 cases (45.3 %), with the lungs being the most frequently affected site (14 cases), followed by the spine (7 cases). Other metastasis sites included the inguinal lymph nodes, ribs, pelvic nodes, breast, prostate, L1 vertebrae, liver, pancreas, and skull, indicating a broader and more varied pattern of metastasis. In contrast, the prior study reported metastasis in 20 out of 85 cases (23.5 %), primarily involving the lymph nodes (6 cases) and lungs (14 cases), with only one case of metastasis to the vertebral column.9 A chi-square test results indicate a chi-square value of 6.89 and a p-value of 0.0087. Since the p-value is less than the alpha level of 0.05, the difference in metastasis rates between our study (45.3 %) and the prior study (23.5 %) is statistically significant. The prior understood rate was 12–29 % (1).This suggests a significant increase in the frequency of metastatic cases in our study compared to the prior study.
7.3 Radiographic findings
The radiographic findings in our study and the prior study reveal both shared characteristics and notable differences in the presentation and structural details of bone tumors. In our study, lesions varied widely, ranging from simple lytic lesions to more complex forms such as finely trabeculated and multi-lobulated osteolytic lesions with a “moth-eaten” appearance. Some lesions displayed well-circumscribed features with mixed sclerotic and lytic characteristics, indicating both bone destruction and formation. Specific cases noted included a lytic expansile lesion with multiple septa and sclerotic margins, and a multi-lobulated osteolytic lesion in the tibia's middle shaft, highlighting the aggressive and diverse nature of these tumors.
Similarly, the prior study documented bone destruction in all cases, with patterns ranging from single areas of destruction to multiple small lucencies within a larger area of destruction. A common feature was the presence of bone sclerosis surrounding these lucencies, often at the periphery of the tumor. 10 % of the lesions were completely lytic with sharp margins, and the involved bone expanded in approximately 90 % of cases. This expansion varied from slight to moderate, with the cortex generally thinned but intact, although around 15 % of tumors had cortical breaks associated with soft tissue masses.9
Our study reports significant cortical involvement, with lesions described as well-circumscribed and often presenting a combination of sclerotic and lytic characteristics. Pathological fractures and cortical breaks were common, indicating severe bone weakening. Examples included lytic lesions with septation and multiple cortical erosions, further emphasizing the tumors' aggressive behavior and potential for significant bone damage.
The prior study also noted extensive cortical and medullary involvement, with most tumors affecting both portions of the bone. In approximately 10 % of cases, lesions were predominantly cortical with minimal medullary involvement. The study highlighted that in most cases, despite the presence of severe destruction, the cortex remained thinned but intact.9 However, in cases where the destruction was most severe, about 15 % of tumors showed cortical breaks and associated soft tissue masses,9 similar to the findings in our study. While both studies highlighted cortical and medullary involvement, our study emphasized the severe bone weakening and aggressive behavior of the tumors more prominently.
Pathological fractures were documented in 13 cases in our study, including one unique case of tumor metastasis to the spine resulting in a fracture. The presence of cortical-based lobulated lesions and eccentric, expansile lytic lesions with cortical breaks further underscored the aggressive nature of these bone tumors and their propensity for causing fractures. The prior study reported pathological fractures in approximately 10 % of cases, with the fractures occurring in bones weakened by disease.9 Soft tissue involvement was noted in 15 % of cases where cortical breaks were present.9 This involvement was characterized by the presence of associated soft tissue masses at the site of greatest bone destruction,9 consistent with the aggressive pathology observed in our study. Both studies highlight the aggressive nature of the tumors, with significant bone destruction, cortical and medullary involvement, and a notable incidence of pathological fractures. Our study provides a broader spectrum of lesion appearances and emphasizes the diversity in radiographic presentations, while the prior study offers a detailed analysis of structural characteristics, bone sclerosis, and expansion patterns. Our study provided a more detailed account of the aggressive nature of these lesions, emphasizing the diversity in radiographic presentations and the complexity of bone involvement.
7.4 Tumor location
In our study, out of 65 cases, 54 were initially found in the appendicular skeleton, while 6 were located in the axial skeleton. Notably, in 4 cases, the tumor migrated from the appendicular to the axial skeleton, with 2 cases specifically spreading to the spine. The tibia was the most common location, with 45 cases (including one case involving both the tibia and fibula). Other locations included the femur and thigh (6 cases), mandible (3 cases), and fibula (2 cases). Additionally, there were single cases involving the pelvis, calcaneal, humerus, vertebra, T11/T12 vertebral bodies, right 7th rib, and tibia to lymph nodes, highlighting a predominant occurrence in the tibia and fewer instances in other locations.
In contrast, the prior study reported the presence of tumors in the tibia in 70 cases (including one case involving both the tibia and fibula), the femur in 6 cases, the ulna in 3 cases, the humerus in 2 cases, the fibula in 2 cases, and the radius in 1 case. Notably, the prior study also documented two separate lesions in the tibia in two cases, one case where the tumor presented initially in the fibula with a subsequent development in the tibia, and one case where the tumor arose in the soft tissue anterior to the tibia without involving the underlying bone. The right side was more frequently affected than the left (34 and 32 cases, respectively), with 19 cases where the side involved was not specified.9
These findings highlight a consistent pattern of predominant tumor occurrence in the tibia across both studies, with the new study showing a broader range of tumor locations and a few instances of tumor migration from appendicular to axial skeleton, including to the spine. This affirms the notion that the tibia is the primary site, however other sites are possible including the axial skeleton.
7.5 Treatment outcomes
In our study, resection procedures had a success rate of 53.6 %, with outcomes such as remission, cured status, and full recovery, while the prior study showed a slightly higher success rate of 64.1 % for excision-resection. This notes a statistically significant decrease in success rates in more recent procedures. Curettage procedures in our study demonstrated a success rate of 62.5 %, compared to a lower success rate of 26.3 % for biopsy-curettage in the prior study.9 Amputation had a success rate of 42.9 % in our study, with a high failure rate due to deaths and recurrences, while the prior study reported a 50 % success rate for amputation,9 indicating some variability in outcomes, but again highlighting a decrease in the success of these procedures over time.
Allograft procedures in our study were the most successful, with a 100 % success rate, which was not specifically addressed in the prior study. Endoprosthetic treatment also showed a 100 % success rate in our study. Among miscellaneous treatments, procedures like surgical excision with curettage and bone graft, resection of rib and hepatic tumor, tumorectomy with spondylectomy, and metastasectomy with cementation each had a 100 % success rate in their respective single cases. Excision with curettage and supervoltage X-ray had a 100 % failure rate. Our study suggests that modern surgical techniques such as allograft and endoprosthesis may provide better outcomes for patients with bone tumors compared to traditional methods used in the prior study.
7.6 Limitations
Some of the limitations of the study is a lack of information on histology due to a lack of consistent reporting by case reports. As a result we are unable to determine the type of adamantinoma and measure the severity of each type. Additionally our dataset was based on case reports which has a possible bias towards more severe cases and does not provide any data toward epidemiology.
8 Conclusion
Adamantinoma is becoming a better understood and complex cancer. Since the 1980s, we have learned of a higher age of diagnosis, multiple histological presentations, a wider array of radiographic findings, a capacity to originate on the axial skeleton, and metastasis to organs aside from lungs. Additionally, we were able to determine a significantly higher metastasis rate than previously understood. However, we note an improvement in treatment outcomes with modern surgical techniques such as allografts with a higher success rate than previous methods such as amputation. We still are not sure as to the origin of Adamantinomas and this will require future study.
Patient consent
Not applicable.
Ethical statement
All procedures performed in this study were in compliance with relevant laws and institutional guidelines. This study did not require ethical approvals as no human subjects were involved in the research. Therefore, no ethical approvals were obtained or needed.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Vijay Patel: Conceptualization, Methodology, Data curation, Project administration, Visualization, Resources, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Santiago Ortiz: Investigation, Writing – original draft, Writing – review & editing. Alessandra Ottley: Investigation, Writing – original draft, Writing – review & editing. Aidan Kaspari: Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Patrick Laird: Supervision, Writing – review & editing. Gary Schwartz: Supervision, Writing – review & editing.
References
- Osteosarcoma: a review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol. 2010 Oct;8(10):705-718.
- [Google Scholar]
- Paediatric osteofibrous dysplasia-like adamantinoma with classical radiological findings. BMJ Case Rep 2018
- [Google Scholar]
- Expression of cytokeratin 1, 5, 14, 19 and transforming growth factors-beta1, beta2, beta3 in osteofibrous dysplasia and adamantinoma: a possible association of transforming growth factor-beta with basal cell phenotype promotion. Pathol Int. 2000 Oct;50(10):801-807.
- [Google Scholar]
- Adamantinoma of long bones: a clinicopathologic study of 85 cases. Cancer. 1989;64(3):730-737.
- [Google Scholar]