Adamantinoma

                                    Dr. KS Dhillon

Introduction

Adamantinomas are rare primary low-grade malignant tumours of the appendicular skeleton. They contain variable epithelial and stromal (osteofibrous) components (1,2). There are several subtypes of adamantinomas. These include classic adamantinoma, osteofibrous dysplasia-like adamantinoma, and dedifferentiated adamantinoma. Adamantinoma accounts for less than 1% of primary bone tumours. The first example was reported by Maier in 1900 (3,4). Fischer in 1913 named the lesion "primary adamantinoma of the tibia" because of its striking histologic resemblance to the jaw "adamantinoma" (ameloblastoma). He described the histology as being similar in nature to that of ameloblastoma of the jaw. A shared histogenic origin, however, has not been proven (5,6).   There are other authors who have also historically reclassified the long bone tumour as a malignant angioblastoma (7,8).

Etiology

There has been much debate over the years about the etiology of this tumour. A variety of sources have suggested several histogenic hypotheses. These hypotheses include synovial, epithelial, or endothelial origin (1,8,9).

Fischer claimed a potential congenital implantation of adamantine epithelial cells in the tibia and the intraoral enamel. Others have speculated about a traumatic implantation of epithelial cells (2,5). Epithelial origin could also be supported by the theory of skin cell basal epithelial displacement during embryological development since the anterior tibia lies in close proximity to the skin surface (4). There is another suggestion that is of a double nature, with the lesions being created by both epithelial elements and spindle cells. This would be similar to a synovial sarcoma (1,8). Changus et al, however, debated against these theories. They additionally highlighted that sarcomatous tumours usually have a more aggressive natural history. Given the lesions vascular nature, this group presented a new concept of primitive vascular mesenchymal cell primary components. They were of the opinion that their designation of angioblastoma presented a better description of a tumour arising from tissue normally present in bone (1,8,10). This was further supported by LLombart-Bosch and Ortuño‐Pacheco. They focused on the differentiation of the mesoderm to form angioblasts, the primary component of blood vessels (7). Adamantinomas contain varying amounts of osteofibrous and epithelial components. Osteofibrous dysplasia is a benign fibro-osseous lesion. There are scattered cytokeratin positive epithelial cells. There has been some debate regarding the evolution of classic adamantinoma from osteofibrous dysplasia to osteofibrous dysplasia like and classical adamantinoma (3,5). This mesenchymal-to-epithelial transformation does present another histogenic hypothesis within a spectrum of fibro-osseous disease (4).

Clinical Presentation

Adamantinoma usually present between the second and fifth decades of life. It is more common in male patients with a male-female ratio of 5:4. It affects the tubular long bones in about 97% of cases. In 80–85% of the cases, it occurs in the mid-portion of the tibial diaphysis. Less commonly it occurs in the metaphysis. In 10–15% of cases it concurrently occurs in the fibula (3,4,5). Other reported sites include the femur, radius, ribs, fibula alone, humerus, ulna, spine, and innominate small bones of the hand and foot (1,11,12).

Although rare, adamantinoma can occur in axial locations. There are two such cases reported in the ribcage (13,14). Dini et al (15) reported a case of spinal adamantinoma. There have been five previous reports including two with concurrent mandibular disease. 

Mosher in 1944 reported a case of adamantinoma in the maxillary sinus. He referenced additional cases in the mandible and pituitary gland (16). There have been several reports of adamantinomas arising exclusively from the soft tissue without any bony involvement. Mills and Rosai, Bambirra, Keeney, and Bertoni reported five cases of histologically identical pre-tibial soft tissue adamantinoma and commented on possible relationships with this pathology’s osseous counterpart (11,17,18,19).  Further cases of ameloblastoma have also been reported in the jaw (20,21). There have also been reports of metastatic suspected ovarian adamantinoma and of concurrent unrelated primary tumors (22,23).

Clinical features

Adamantinomas present with non-specific slowly progressing symptoms and have an indolent course. The symptoms most commonly include swelling, pain, erythema, local sensitivity, bowing deformity, an inability to bear weight, and limping (24-26). In about 60% of cases, there will be a history of previous trauma to the area. Severe paraneoplastic, humorally mediated hypercalcemia, pancreatitis, and hypercalcemic coma, have also been reported secondary to adamantinoma (3,5).

Differential diagnoses

For adamantinoma of the long bones, the differential diagnoses would include (3,19):

• Osteosarcoma

• Metastatic carcinoma

• Ewing’s sarcoma

• Aneurysmal bone cyst

• Unicameral bone cyst

• Eosinophilic granuloma

• Osteomyelitis

• Chondrosarcoma

• Osteofibrous dysplasia

• Fibrous dysplasia

• Epithelial metastases

• Haemangioendothelioma

• Haemangiosarcoma

• Non-ossifying fibroma

• Chondromyxoid fibroma 

Radiological diagnosis

According to Jain et al, a lesion affecting the diaphysis including the anterior cortical bone with extension toward the bone marrow is diagnostic of adamantinoma. Approximately 16–23% of cases have a concurrent pathological bone fracture (4,26). Common radiological features include a central or eccentric osteolytic multilocular lesion with well-circumscribed sclerotic margins. The well-circumscribed sclerotic margins indicate slow growth. Eventually, there is endosteal scalloping and thinning with cortical destruction. Overlapping radiolucencies can create a soap bubble appearance in the diaphysis or metaphysis (12). The mass can be expansile. It can have variable delineation and septations as well as homogenous enhancement and inclusion of the medullary canal. It usually is intra-cortical.  In approximately 15% of cases, it invades the surrounding soft tissues. A concurrent fracture can produce a periosteal reaction. The lesions can appear in single or multiple nodules in one or more foci (1,5). 

Other imaging modalities can also be used for diagnosis. Computed tomography can be useful for assessing cortical involvement and metastatic disease. Magnetic resonance imaging is the gold standard. It further delineates distant foci and soft tissue and intramedullary extension. It is particularly useful to guide staging and surgical treatment options. Nuclear medicine scans will demonstrate increased blood flow and pooling around the lesion with technetium-99 m methylene diphosphate accumulation. Positron emission tomography can also identify FDG avid disease across other sites (4,5,23).

Pathological diagnosis

Histopathological diagnosis is established through the use of biopsies. The biopsies should always be extensive and should be obtained from the most radiolucent areas. The biopsies can be taken with the use of CT or ultrasound guidance. Results are interpreted in combination with radiological findings. A multidisciplinary team approach is required for appropriate management (3,4).

Adamantinoma is categorized into classical, osteofibrous dysplasia-like (differentiated), and dedifferentiated histological sub-types. Adamantinomas are bland pale-colour tumours of variable consistency. They may contain cystic spaces in which there is straw or blood-like fluid. Differentiated adamantinoma can be distinguished histologically from classical adamantinoma. It contains relatively few epithelial cells, some of which lie in small collections or nests. Osteofibrous dysplasia–like adamantinoma is commonly seen in younger people. It has a higher proportion of centrally located osteofibrous stromal tissue and it lacks a clear histological epithelial component (27,28). This type tends to be less destructive, multicentric, and remains intracortical (3,5,29). Classical adamantinomas are seen most commonly. They have a prominent epithelial component which cytologically may be mixed in type (12,30). Very rarely there can be de-differentiation of a classical adamantinoma to a sarcoma containing pleomorphic or round tumour cells. There are rare reports of high-grade cancerous transformation to squamous cell cancers within the adamantinomas (31).

On microscopic examination, epithelial tumour cells vary in size and they have finely dispersed chromatin with few mitotic figures. The osteofibrous component has a storiform pattern of spindle cells. They also have woven bone trabeculae with varying amounts of lamellar bone transformation at the peripheries and foam cell or myxoid change. The spindle cell component is usually seen in recurrences and metastases (1,4).

Moon and Mori in a series of 195 cases used immunohistochemical (IHC) and ultrastructural studies to further the argument for an epithelial origin. The epithelial cells may represent active neoplasm within the adamantinomatous lesions. The fibrous component shows little expression, suggesting a potential reactive surrounding growth. There are several authors who have demonstrated that there is epithelial cell basal keratin, growth factor, and fibrous vimentin staining regardless of lesion subtype. This has also been seen in metastasis and recurrences. There are other features including epithelial-like microvilli and tonofibrils forming the desmosomes, which are indispensable for cell-to-cell attachment. Electron microscopy has shown cells to have further epithelial characteristics such as basal lamina, gap junctions, and extracellular composition (1,2,4). These findings have been contradicted by Llombart-Bosch and Ortuño‐Pacheco. They reported a lack of desmosomes and evidence of pinocytic activity with bundles of filaments resembling hyperplastic endothelial cells. They noted fibrolipoblastic lipid-laden mesenchymal cells within the stroma (7).

Further IHC investigation has shown that adamantinomas are positive for cytokeratins 5, 14, and 19. There is variable expression of cytokeratins 1, 13, and 17. There is virtually no expression of cytokeratins 8 and 18 (4,32). There is vimentin in the stromal component. IHC studies by examining flow cytometry and p-53 expression demonstrated up to 48% expression of p53 proteins in all classical subtypes (33,34). P-63 is a reliable marker in adamantinomas (35). E-, P- and N- cadherin and osteonectin are expressed in the classical subtype. In OFD adamantinoma there is expression of nuclear factor kB ligand, macrophage cerebrospinal fluid, and osteoclastogenic factors (29,36). Trisomies of chromosomes 7, 8, 12, 19, and 21 have been demonstrated through GTG-banding in both classical and OFD adamantinomas. This substantiates the common histological origins. Findings of translocations, deletions, and inversions are only present in adamantinomas (1,8,33,37). A rare variant of adamantinoma-like Ewing sarcoma has been described. This is now known to be molecularly distinct. It is in fact an Ewing sarcoma that exhibits some histological features of adamantinoma. It can be differentiated based on the classical translocation characteristics of Ewing sarcoma t(11; 22) and t(21; 22) using reverse transcription polymerase chain reactions (38).

Microscopic findings by Huvos and Marcove have further supported the angioblastoma theory. A series of 85 cases were reported by Keeney et al, which commented on an unusually prominent vascular pattern in the lesions histologic appearance (10,11). Structures similar to endothelial Weber-Palade bodies and alkaline phosphatase have also been demonstrated. Changus et al to further support the nomenclature of malignant angioblastoma of the bone went so far as to achieve a review and histological reclassification of 25 cases of adamantinoma of the long bone based on the authors’ descriptions. They also highlighted the abnormal vascular channels within these tumours. They focused on similar histochemical reactions compared to normal blood vessels.

Metastatic disease

Metastases occurs in 15–30% of patients through lymphovascular routes. Most often metastases occur in the regional lymph nodes and lung. Less frequently it is seen in the bone, abdominal viscera, and retroperitoneum (22,26). There is a wide variation in the reported rate of lymph node metastases. Keeney et al. documented a 7% risk, whilst Moon and Mori found lymph node metastasis in up to 28.6% in their post-mortem examinations (2,11). Schowinsky et al reported a patient with a potential ‘secondary’ metastasis to the brain from a metastatic lung nodule, 32 years following surgical excision of adamantinoma of the tibia (5,23,39).

Recurrences and metastases can occur after long periods of time. There are cases reported where recurrences and metastasis occurred up to 36 years after initial treatment. 

One such example is seen in a report by Giannoulis et al. They reported a 46-year-old patient who developed both multiple early recurrences in the tibia and late metastasis to the lung and ribs 13 years later. This protracted course of recurrence and reported overall low-grade malignant potential is however not always the case. Binesh et al in 2012 highlighted such an example. They reported that a 19-year-old male died within weeks of diagnosis and initial surgery to eradicate an adamantinoma of the pelvis. He died due to acute liver failure secondary to widespread metastases (3,25,40).

It is very important to remain vigilant for potential diagnoses of incidental unrelated primary concurrent cancers. Such a case has been reported twice in the literature. In one case a chromophobe-type renal cell carcinoma was diagnosed following partial nephrectomy for presumed adamantinomatous metastasis and in another case, there was a metastatic adamantinoma alongside primary concurrent breast cancer (22). This consideration emphasizes the role of the MDT in decision-making regarding the diagnosis and management of such lesions. When considering potential metastases, there are significant challenges regarding interpreting investigations about the site and origin of the disease. In such situations, the clinician might consider ruling out a genetic predisposition to cancer (4,23).

Surgical management of primary and recurrent disease

Patients are often under the clinical management of the sarcoma MDT with primary management input from orthopaedics and management of pulmonary disease by thoracic surgery, amongst other specialties. The standard treatment for adamantinoma of long bones is en-bloc resection with wide surgical margins, aiming for complete excision in an effort to reduce the chances of local recurrence of this locally aggressive tumour [2], [11], [40], [41]. Limb salvage with intercalary resection and reconstruction either with bone transport, free vascularized fibular graft, allograft, or endoprosthetic reconstruction can be attempted [1], [3], [42]. More rarely the treatment to get adequate resection margins would require limb ablative surgery followed by the use of limb prosthesis. Locoregional lymph node dissection should also be considered at the time of primary tumour resection. Intralesional surgery such as curettage and cementing is not recommended.

Most patients are treated with limb salvage. The need for reoperation is significantly high at 39% in one review. The need for reoperation is mostly due to surgical complications (9). Qureshi et al (42) carried out a retrospective study that was designed to evaluate the clinical outcomes of limb salvage operations for the treatment of adamantinoma. They obtained data on seventy biopsy-proven cases of adamantinoma treated between 1982 and 1992 at 23 different cancer centers in Europe and North America. Ninety-one percent of the patients had attempted limb salvage and 51% had an intercalary allograft reconstruction. The final preservation rate was 84%. Eight percent of the patients later required amputation. Wide operative margins were achieved in 92% of the patients. Reconstruction related complications occurred in 48% of cases. Allograft fracture occurred in 24% of the patients and non-union occurred in 23% of cases. Infection occurred in 10%, unspecified soft tissue complications in 3%, and delayed union in 3% of the patients. Adamantinoma is locally aggressive. With Kaplan-Meier analysis local recurrence was documented at a rate of 8.6% at 5 years and 18.6% at 10 years. This was not statistically significant regarding relationship to stage (3,9,42). Houdek (9) documented a 10-year disease-specific and recurrence-free survival of 92 and 72% respectively. In cases of incomplete resection, local recurrence is still more common as with sarcomatous tumours. Amputation does not improve outcomes in primary tumours. It is reserved for instances of local recurrence (5,40). Care should be holistic and should include physiotherapy, prosthetics and cancer nurse specialists and allied healthcare professionals (4).

The European Musculoskeletal Oncology Society (EMSOS) recently published a large international multicentric study spanning 30 years and 22 tertiary centers. This study included 190 cases of adamantinoma. There is limited data available to support current treatment strategies. Local recurrence was recorded in 24% of cases. A proportion was felt to be due to undetected skip lesions as well as the possible presence of periosteal disease. There is a need for aggressive wide surgical excision with clear margins (26).

Adjuvant therapy

There has been no demonstrated role for the use of adjuvant therapies unlike in metastasizing ameloblastoma. This information is based on a summary of case reports. It does not appear to have been investigated in clinical trials; owing to the rarity of this pathology (10,26). There is significant merit in obtaining input from medical and clinical oncology specialists. Hazelbag et al reported on patients with metastatic disease receiving chemotherapy who did not achieve any benefit regarding tumour volume or survival. Three other authors reported disease stability at best with chemotherapy and radiotherapy followed by subsequent progression across a matter of months in three cases (43-46). J. Lokich reported the only discernable case of disease regression. There were two separate occasions when a patient with metastatic adamantinoma of the bone to the lung responded to combinations of etoposide with cisplatin and then carboplatin. The same patient responded again to palliative radiation, resulting in a protracted duration of metastatic disease over three years (47).

Prognosis

Some of the factors associated with a less favorable clinical outcome include (11,39):

• Male gender

• Short duration of symptoms particularly with predominating pain

• Younger age at presentation

• Histological lack of squamous differentiation

• Intraregional treatment modalities.

According to EMSOS the resection margins, incidence of pathological fracture, and patient gender significantly contributed to local recurrence risk (26). There has been no statistically significant difference between local recurrence rate and tumour stage, type of biopsy, or method of graft reconstruction used. In a series of 92 patients Aytekin et al found that survival time was independent of gender, age groups, race, marital status, tumor location, and year of diagnosis. There was another reported case of adamantinoma with aggressive pulmonary and liver metastases that further postulated on possible improvement in overall outcome based on cellular malignant potential at biopsy. The author found dense cell proliferation without interstitial tissue and dominant epithelial parts. They were of the opinion that if recurrences and metastases were under control, resection should be curtailed to include only newly appearing high-grade lesions (3,41,42,48). In 11% of the cases, adamantinoma has been reported to be fatal (26). There has been a five and ten-year overall survival rate of 98.8% and 91.5%. Patients generally have an excellent prognosis (48).

Follow up

Since there are late recurrences and metastases, all patients require long-term follow-up. Some authors suggest that this should be life-long. There is paucity of evidence regarding the best modality of follow-up imaging and surveillance intervals (4,11,25). In the Houdek et al case series of admantinomas, 42% of patients with distant metastatic disease focused on abdominal recurrences or pelvic lymphadenopathy. This indicates consideration for abdominopelvic CT or PET scans. The same authors reported that their current practice included only MRI of the involved extremity and chest CT for 10 years (9). Most authors recommend regular clinical and radiograph follow-up focusing on MRI or radiograph of the extremity. Some suggest surveillance chest radiographs, chest CT, or whole-body MRI. EMSOS emphasized the need for long-term follow-up of twenty years or more using chest and local radiographs or MRI of the surgical site. Eleven percent of their cases of local recurrence were diagnosed more than ten years following initial treatment (26). There is a need for a more or less intensive individualized action plan (3,23,24,39). 

Conclusion

Adamantinoma is a rare long-bone tumour of uncertain origin. Late recurrences and metastases often occur. There are complex nonspecific presentations. There is a need for careful consideration and planning with a full complement of specialist knowledge and expertise. The nature of this tumour is heterogeneous. It presents challenges regarding diagnosis and treatment. The MDT approach is required to direct and achieve appropriate treatment. Complete resection and reconstruction should be carried out with wide surgical margins where possible. There is a lack of structured guidance regarding appropriate follow-up and surveillance. There is a need for an individualized approach taking into consideration the patient’s disease course.

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