Abstract
A dedifferentiated adamantinoma is a rare subtype of an adamantinoma, associated with a relatively aggressive clinical course, with less than 10 such cases reported so far. A 25-year-old-male presented with pain in his right leg of 1-year duration. Imaging disclosed a well-defined lytic, destructive lesion in his proximal tibia with a cortical break and a soft tissue component. Microscopic examination of the biopsy and resected specimen showed nests and clusters of atypical epithelial cells, along with significant areas showing markedly pleomorphic and spindly sarcomatous cells with interspersed mitotic figures and areas of stromal hyalinization. By immunohistochemistry, the areas of epithelial differentiation showed intense positivity for cytokeratin and p63, whereas the sarcomatous areas showed reduced to absent immunostaining. A 51-year-old lady presented with a recurrent tumor in her right tibia, which was initially diagnosed as an adamantinoma, along with metastatic lesions in her lung. Microscopic examination of the recurrent and metastatic tumors showed areas of epithelial differentiation along with spindly sarcomatous cells, arranged in fascicles. By immunohistochemistry, the areas of epithelial differentiation showed positivity for pan cytokeratin. Additionally, p63 was diffusely positive. p53 showed diffuse and intense staining pattern in the sarcomatous component (dedifferentiation). While the first case is disease-free, the second case is on follow-up. The 2 cases of dedifferentiated adamantinoma further confirm the rare occurrence of this tumor in our population. Its correct diagnosis has treatment implications. Differential diagnoses and literature review of similar reported cases are also presented in this article.
Keywords
Introduction
An adamantinoma is defined as a malignant biphasic tumor, characterized by various morphologic patterns, mostly clusters or aggregates of epithelial cells, surrounded by a relatively bland spindle cell stroma. It occurs over a wide age range, mostly in patients within the age of 25 to 35 years, including anterior tibial metaphysis or diaphysis as it is the most site of occurrence. 1
On radiologic imaging, it invariably appears as a well-circumscribed, cortical-based, lytic lesion, which can be destructive and invade into the medullary cavity and/or the adjacent soft tissues. On histopathologic examination, it has 2 components, namely, epithelial and osteofibrous. Various patterns of epithelial differentiation occur in varying proportions, including basaloid, spindle cell, tubular, squamous type, or osteofibrous dysplasia (OFD)-like, with spindle cell pattern more frequently seen in recurrent or metastatic lesions.1,2 The osteofibrous component, which is also considered as a differentiated form of an adamantinoma, is composed of relatively banal looking cells with fewer mitotic figures.
Over the years, the clinicopathologic spectrum of an adamantinoma has expanded, with identification of another subtype, namely, a dedifferentiated adamantinoma. On histopathologic examination, this is characterized by areas of classic adamantinoma, juxtaposed with tumor areas comprising highly pleomorphic, sarcomatous cells; increased number of mitotic figures; and, in certain cases, osteoid formation.3-5 These tumors are known to have a relatively aggressive clinical course. 3 At the same time, these tumors need to be differentiated from their mimics, such as synovial sarcomas, metastatic carcinomas, osteosarcomas, and intraosseous myoepithelial tumors.6-9
Case 1
Clinical History
A 25-year-old male presented with complaints of progressively increasing pain in his right leg of 1-year duration. He felt an increase in the pain during exertion and prolonged walking.
On clinical examination, a diffuse swelling was noted in the proximal one third of his right leg, localized over the anterior and lateral compartments. His range of movements at the knee and ankle joints was normal. There were no distal vascular deficits.
Plain radiograph showed a well-defined lytic, destructive lesion in his proximal right tibia, associated with a soft tissue component (Figure 1A).
Case 1. (A) Plain radiograph showing a well-defined, cortical-based, lytic, destructive lesion in the metaphysis of right tibia. (B). Magnetic resonance imaging showing a well-defined lytic, destructive lesion in the metaphysis of right tibia with cortical break and a soft tissue component.
Magnetic resonance imaging (MRI) showed a well-defined eccentric, lobulated soft tissue mass, arising from the proximal anterolateral metaphysis of the right tibia, encasing the patellar tendon and causing eccentric tibial cortical destruction with intramedullary extension, along with a large soft tissue component reaching up to the overlying skin. The tumor mass was associated with moderate marrow edema in the proximal tibia (Figure 1B). The radiologic impression was of a nonossifying fibroma.
There was no other lesion detected elsewhere with positron emission tomography.
His laboratory investigations showed increased serum alkaline phosphatase levels (124 U/L, normal range = 30-120 U/L) and increased lactate dehydrogenase levels (194 U/L, normal = 100-190 U/L).
He underwent a biopsy, followed by a wide excision, including resection of the proximal tibia by lateral approach with nerve repair, followed by total knee replacement. Four months postexcision, the patient is free-of-disease and is on follow-up.
Pathologic Findings
Grossly, an excised specimen was received measuring 11 cm × 8 cm × 7 cm, comprising tibia, including its proximal articular end, along with the attached fibula measuring 5.5 cm in length. On external examination, a lump was noted at the proximal end of the metaphyseal region of right tibia, measuring 8.5 cm × 8.5 cm × 2.5 cm. Cut surface showed a gray-white, firm tumor measuring 8.7 cm × 6 cm × 4 cm, involving the tibia, with a cortical breach toward its anterolateral surface.
Microscopic examination of the biopsy and resected tumor showed nests and cords of atypical epithelial cells, reminiscent of a classic adamantinoma, along with conspicuous areas displaying spindly and markedly pleomorphic cells with interspersed mitotic figures, including atypical forms. Additional sections from the resected tumor showed prominent areas of hyalinized matrix, along with few scattered osteoclast-like giant cells, indicative of a high-grade sarcomatous dedifferentiation (Figure 2A-D).
Case 1. Microscopic features (A-D). (A) Cellular tumor composed of nests, groups, and clusters of atypical epithelial cells within a cellular stroma (hematoxylin-eosin [H&E], ×200). (B) Sections from resected tumor showing areas of epithelial differentiation, juxtaposed with areas of pleomorphic, spindly, sarcomatous tumor cells (asterisk; H&E, ×200). (C) Areas showing several multinucleate and atypical spindly cells with interspersed mitotic figures, reminiscent of sarcomatous dedifferentiation (H&E, ×400). (D) Sarcomatous areas with prominent stromal hyalinization (H&E, ×400).
By immunohistochemistry, the epithelial component of the tumor showed diffuse positivity for pan cytokeratin (AE1/AE3), CK5/6, and p63, whereas the juxtaposed sarcomatous areas displayed reduced to absent staining for these immunohistochemical antibody markers. In addition, the tumor cells in the areas of epithelial differentiation displayed positivity for cytokeratin (MNF116) and high-molecular-weight cytokeratin (HMWCK) and negativity for epithelial membrane antigen, S100 protein, glial fibrillary acid protein (GFAP), desmin, CD34, and CD31. Mib1/KI67 highlighted 30% to 40% tumor nuclei, including both differentiated and sarcomatous areas. Tumor cells showed complete absence for p53 immunostaining (Figure 3A-D).
Case 1. Immunohistochemical staining results. (A). Epithelial cell clusters and nests showing intense cytoplasmic staining for pan cytokeratin (AE1/AE3; diaminobenzidine [DAB], ×200). (B) Higher magnification: epithelial cell cluster showing AE1/AE3 immunostaining, with sarcomatous stromal cells showing its weak to absent staining (DAB ×400). (C) Epithelial cell clusters displaying positive immunostaining for CK5/6 (DAB, ×400). (D). Epithelial component showing intense positivity for p63, with stromal component displaying its reduced to absent staining (DAB, ×200).
Diagnosis of dedifferentiated adamantinoma, offered on biopsy, was further confirmed on the resected specimen. Various cut margins were free of tumor.
Case 2
Clinical History
A 51-year-old lady presented with a history of a recurrent tumor in her right leg, for which she underwent a curettage procedure, 6 years ago.
During her recent clinical examination, a scar was noted over her right leg, indicative of the previous surgery, along with a nodule toward its medial side.
Her serum alkaline phosphatase level (103 U/L) was within the normal range.
She underwent detailed radiologic imaging, followed by tumor resection. Currently, she is receiving adjuvant chemotherapy.
Her preoperative MRI showed an altered marrow intensity lesion in the mid diaphysis of her right tibia, extending for a craniocaudal length of 4 cm. It was located at a distance of 12 cm from the proximal tibial articular surface and 12 cm from the distal tibial articular surface. It was associated with cortical thickening and focal cortical break along with an anterior extraosseous soft tissue measuring 2 cm × 1.1 cm in maximum axial dimensions. The soft tissue component was seen abutting the tibialis anterior muscle and extending toward the skin surface. The lesion appeared hypointense to isointense on T1W images, hyperintense to muscle on T2W/STIR sequences, and showed heterogeneous postcontrast enhancement (Figure 4A-B).
Case 2. (A) A plain radiograph showing a sclerotic lesion in the diaphysis of right tibia with a soft tissue component. (B) Magnetic resonance imaging showing an altered marrow signal intensity lesion in the diaphysis of tibia with a soft tissue component.
Positron emission tomography-computed tomography scan showed a lytic, hypermetabolic lesion in the right tibia and a subcutaneous nodule, toward its anterior side, likely representing residual primary tumor with a maximum standardized uptake value of 8.1, along with another hypermetabolic lesion in the upper lobe of right lung with a maximum standardized uptake value of 9.1.
Her initial biopsy and recurrent lesions were diagnosed as an adamantinoma. Subsequently, she underwent right tibial intercalary resection, along with pulmonary metastatectomy.
Grossly, a specimen of right tibial intercalary resection was received, measuring 17 cm × 6 cm × 3.5 cm, with a skin flap measuring 10 cm × 3.5 cm on the anteromedial aspect. Serial sectioning revealed a grayish-brown tumor measuring 2.4 cm × 1.5 cm × 1.4 cm, significantly in the anterior soft tissues and was seen reaching up to the overlying skin.
Serial sectioning of the right lung metastatectomy specimen revealed a gray-white tumor measuring 2.5 cm × 2.4 × 2.0 cm. The tumor was seen sparing the pleura.
Microscopic examination of the recurrent and the metastatic tumor specimens showed similar morphologic features. The tumor was composed of polygonal cells arranged in cords and nests, juxtaposed to atypical spindle cells arranged in short fascicles, diffusely and in “herring bone-like” growth patterns. Individual tumor cells were oval to spindle shaped with scant cytoplasm and hyperchromatic nuclei. Interspersed were frequent mitotic figures, ranging from 8 to 10/10 high-power fields, along with focal myxoid change (Figures 5A and B and 6).
Case 2. Microscopic features (A and B). (A) Nests and cords of tumor cells juxtaposed with areas showing spindle cell proliferation (hematoxylin-eosin [H&E], ×400). (B) Sarcomatous component comprising spindly cells arranged in interlacing fascicles (H&E, ×200).
Section from the pulmonary metastatectomy specimen showing spindly sarcomatous tumor cells with focal mucinous stroma. Hematoxylin-eosin, x200.
By immunohistochemistry, pan cytokeratin (AE/AE3) was patchily positive, especially in the epithelial component, while negative in the spindly sarcomatous component. Vimentin also showed patchy immunostaining pattern. Epithelial membrane antigen was focally positive. p63 was diffusely positive. p53 was strongly and diffusely positive in the spindly sarcomatous areas, while it was focally positive in the areas of epithelial differentiation (Figure 7A-D). CK5/6, BCL2 MIC2, S100 protein, and GFAP were negative in the tumor cells. INI1/SMARCB1 was diffusely retained (Table 1). Diagnosis of a dedifferentiated adamantinoma was offered. Various soft tissue and bony cut margins were free of tumor.
List of Various Antibody Markers Used in the Present Study.
Case 2. Immunohistochemical staining results. (A) Tumor cells showing focal positivity for AE1/AE3 in the epithelial component (diaminobenzidine [DAB], ×200). (B) Diffuse positivity for p63 (DAB, ×200). (C) Focal positivity for p53 in the epithelial component (DAB, ×200). (D) Diffuse, intense positivity for p53 in the sarcomatous (dedifferentiated) component (DAB, ×200).
Discussion
A dedifferentiated adamantinoma is an extremely rare subtype of an adamantinoma with less than 10 such cases reported so far, to the best of our knowledge. All these cases were identified in the Western population (Table 2).3-5,10 Herein we describe 2 cases of dedifferentiated adamantinomas, constituting first such documentation from our region. An earlier published series of 12 adamantinomas, diagnosed over a period of 23 years at our Institution, included a single metastasizing tumor, with no case of a dedifferentiated adamantinoma. 11
Review of Literature Regarding Reported Cases of Dedifferentiated Adamantinomas.
Abbreviations: AWNED: alive with no evidence of disease; DOD, died of disease; CT, chemotherapy; RT, radiation therapy; NK, not known; AWD: alive with disease.
Presented with a recurrent tumor and metastasis.
Dedifferentiated adamantinomas have been mostly reported in the tibia (78% cases), either as de novo or as recurrent tumors, in patient with age ranging from 21 to 83 years (average = 51, median = 40), as noted in the present cases.3-5,10 Rarely, this tumor has been reported with a coexisting fibrous dysplasia. 5 On radiologic examination, these tumors invariably appear as cortical-based, lytic lesions, similar to a classical adamantinoma. In case of metaphyseal tumors, a nonossifying fibroma (as considered in the first case of this study) constitutes as a differential diagnosis on imaging. MRI can be useful in identifying an aggressive pattern of this tumor, along with its extent, as noted in an earlier reported case. 5
A definite diagnosis is made on histopathologic examination. Apart from areas of epithelial differentiation, the dedifferentiated component is seen in the form of a high-grade sarcoma, including a pleomorphic sarcoma, an osteosarcoma, with chondroblastic differentiation, and a spindle cell sarcoma. Among these, osteosarcomatous dedifferentiation has been most frequently reported in dedifferentiated adamantinomas.3,10 We observed pleomorphic sarcomatous pattern, including areas of hyalinization in the first case and spindle cell sarcomatous component in the second case, the latter pattern reported by Izquierdo et al 4 and Nouri et al 5 in their 2 distinct reported cases, respectively. Dedifferentiated adamantinomas containing several osteoclast-like giant cells have also been reported.3,10 A definitive diagnosis requires application of immunohistochemical stains, as noted in the various reported cases, including the present study. Pan cytokeratin (AE1/AE3) is the most frequently observed positive epithelial immunohistochemical marker, including in the present 2 cases. In the first report of dedifferentiated adamantinomas, Hazelbag et al 3 described positive expression of various types of cytokeratins, including their pattern of expression. They observed basal type of epithelial differentiation (CK14, CK19, and HMWCK) in all their 3 cases, along with variable glandular differentiation (CK8/18) in primary versus dedifferentiated, recurrent tumors. They observed reduced to absent staining pattern for cytokeratins in areas of sarcomatous dedifferentiation, as noted in the present study. Izquierdo et al 4 reported an extreme pattern of dedifferentiation, with epithelial cells displaying positive immunostaining for cytokeratin and the sarcomatous cells showing compete loss of the same (biphasic pattern). In addition to the epithelial markers, Hazelbag et al 3 observed EGFR positivity in their cases, which they considered as indicative of paracrine stimulation of fibrous cell growth. Furthermore, in congruence with their results, we observed diffuse strong p53 immunostaining in one of our cases (in the sarcomatous areas) and complete absence in the other (mutation type). 3 In another earlier study, Hazelbag et al 12 reported moderate to strong immunohistochemical staining for p53 in 12 out of 25 cases (48%) of adamantinomas, restricted to the epithelial cells. Furthermore, they recognized loss of heterozygosity at the p53 focus in the epithelial component of an immunohistochemically p53-positive tumor. While they did not observe p53 immunoreactivity in OFD-like adamantinomas, they observed p53 immunoreactivity in a recurrent OFD-like adamantinoma and a classic adamantinoma. Diffuse expression of p53 in the sarcomatous component in one of our cases of dedifferentiated adamantinomas indicates its possible role in the process of dedifferentiation, apart from its role as a late event in the development of an adamantinoma, as suggested previously.3,12
Besides cytokeratins, p63 has been reported as a consistent immunohistochemical marker for diagnosing adamantinomas. 13 We observed relatively more intense p63 immunostaining in the epithelial component of the first tumor and its reduced to absent expression in the sarcomatous component. In our second case, we observed diffuse p63 immunostaining in both the components. Vimentin was patchily positive within the tumor cells, reinforcing the concept of mesenchymal transition within this tumor. 10 The term “dedifferentiation” is considered as loss of epithelial differentiation and replacement by a sarcomatous component, similar to an epithelial-mesenchymal transition. Furthermore, this term is considered in contrast with a differentiated adamantinoma. With regard to its origin, there have been strong arguments favoring association between an OFD and a classic adamantinoma, with possibility of the former lesion being a precursor of the latter.10,14 In fact, the presence of an OFD-like pattern in a “differentiated” adamantinoma was considered as a feature indicative of spontaneous regression in this tumor. 15 Furthermore, detection of common cytogenetic features, such as trisomies of 7, 8, and 12 chromosomes in certain cases of classic adamantinomas and trisomies of 7 and 8 chromosomes in 1 out of 2 cases of OFD-like adamantinomas, indicates a common histogenesis between an OFD and an adamantinoma. 16 Lately, identification of positive immunoexpression of podoplanin, an osteocyte marker, in epithelial component of adamantinomas, as well as in scattered intertrabecular stromal cells in both adamantinomas and OFDs, by Kashima et al 17 further reinforces a common histogenetic proximity between the 2 entities. However, in another study, Sweet et al 18 did not observe any other cases of cortical OFD developing into an adamantinoma, despite overlapping clinicopathologic features between the 2 lesions. p63 immunostaining, observed in both cases of the present study, has been reported in both classic and differentiated adamantinomas. 13
Apart from certain clinic-radio-pathologic features, immunohistochemical markers are also useful in differentiating this tumor from its mimics. The differential diagnoses in the present study included a metastatic carcinoma; an osteosarcoma, especially in the first case; a synovial sarcoma, especially in the second case; and intraosseous myoepithelial tumors, including carcinomas. In view of lack of primary lesion, elsewhere, on imaging, along with aforementioned histopathologic and immunohistochemical features, a metastatic carcinoma was ruled out. Despite areas of dense hyalinization, suggestive for osteoid formation, in the first case, presence of distinct areas of epithelial differentiation made diagnosis of a primary osteosarcoma less likely. Synovial sarcoma was a close differential diagnosis in the second case, as similarly observed by Izquierdo et al 4 and Nouri et al. 5 Diffuse p63 immunostaining, coupled with lack of BCL2 immunoexpression and retained INI1 expression, made this diagnosis less likely.19-21 Due to logistic constraints, molecular test for SS18 rearrangement could not be performed in the second case. In spite of positive immunoexpression of epithelial antibody markers, lack of S100 protein and/or GFAP immunoexpression ruled out possibility of intraosseous myoepithelial tumors.9,22,23 Lack of SMA and desmin ruled out a leiomyosarcoma, and loss of S100 protein expression ruled out a melanoma, as observed by others.3,4
An exact diagnosis in such a case has diagnostic implications. Surgical resection with clear margins constitutes the treatment mainstay, as noted in the present cases.3-5Adjuvant radiation therapy may be considered in cases of incomplete resections for an improved loco-regional clearance. Chemotherapy does not seem to offer additional benefit, as it is offered in cases with recurrences and metastasis, the latter constituting as an adverse prognostic parameter in these tumors.3-5,10 Diagnosis of a metastatic carcinoma would lead to consideration of an adjuvant chemotherapy. Similarly, diagnosis of an osteosarcoma or a synovial sarcoma would lead to consideration of specific chemotherapy regimens, which were not offered in either of our 2 cases.
There is no molecular signature for this tumor so far. However, in a relatively recent study published as a conference proceeding, Tirabosco et al 10 reported a substitution in H3F3A mutation involving p.G34W, a mutation described in 95% giant cell tumors, in the dedifferentiated adamantinoma with osteoclast-rich component. Whereas one of the initial cases reported by Hazelbag et al 3 had numerous osteoclastic giant cells, our first case showed few osteoclast-like giant cells in the sections from the excised tumor.
To conclude, our 2 cases further confirm the presence of this rather unusual and relatively aggressive variant of an adamantinoma in our population. Its differentiation from its diagnostic mimics has therapeutic implications. There is a possibility of involvement of p53 gene in the development of some cases of dedifferentiated adamantinomas. It would be worthwhile studying cytogenetic features of dedifferentiated adamantinomas, in order to understand their evolution and possible link with an adamantinoma.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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