The radiographic features of ABC are quite distinct and aid in diagnosing the disease. Conventional radiographs show an eccentric radiolucent lesion with expansile remodeling of bone. A thin surrounding rim of the periosteum and sub periosteal bone is usually present. The cyst wall trabeculae impart the multilocular appearance (Fig. 1). In the vertebral column, ABC most commonly involves the posterior neural arch and can produce an eccentric “blowout” lesion [3]. In small tubular bones of hands and feet, the characteristic “finger-in-the-balloon” sign might be present.

Computed tomography shows a well-delineated lytic lesion, usually with a thin surrounding rim of reactive bone (Fig. 2A). Occasionally, fluid-fluid levels are visible. However, the best imaging modality to identify the fluid-fluid levels is magnetic resonance imaging. The cysts usually demonstrate variable signal intensity with a rim of low T1 and T2 signal. T1 post-contrast sequence may show some enhancement of septations (Fig. 2B–D) [13,14].

Isotope scan shows a peripheral uptake with central photopenia, which imparts a “donut sign” appearance. This appearance is not specific for ABC and can also be seen in other bone lesions with ABC-like changes such as chondroblastoma and giant cell tumor of bone.

Grossly, an ABC appears as a well-demarcated spongy hemorrhagic lesion with variably-sized multiloculations. The cystic spaces are variable in size ranging from less than one millimeter to several centimeters [3]. It has irregular, sharply demarcated borders with a thin shell of reactive bone around it. A variable amount of solid component might be present, particularly in the digits (Fig. 3).

When encountered in an intraoperative consultation (frozen section), ABC is characterized by small fragments of cellular septa containing fibroblast-like stromal cells, osteoclast-like giant cells, and reactive woven bone that frequently displays osteoblastic rimming. While mitoses are typically easily identified, atypical mitoses and cytologic atypia are not present, and when these features are encountered on a frozen section they warrant a detailed discussion with the surgeon (Fig. 4).

ABC is almost always received as curetted material rather than an en-bloc resection. As a rule, the curetted material must be entirely submitted for histologic evaluation. Low-power microscopic examination shows a multiloculated cystic lesion with collapsed cyst walls within the background of blood and hemorrhage. The septa show mixed inflammatory cells, reactive fibroblasts, woven bone, and some vasoformative foci; however, the cyst walls lack a true lining. Characteristic calcified basophilic material, referred to as “blue reticulated chondroid-like material” might be present within the cyst walls [15]. The cysts are generally devoid of any lining but some flattened endothelial-like cells can be present. Osteoclast-type giant cells are found in clusters with increased numbers within the cyst wall. Mitoses can be easily identified, but atypical mitoses are not. Necrosis and cytologic atypia are not the features of ABC (Figs. 5, 6). There is no specific immunohistochemical stain for the diagnosis of ABC.

Recurrent rearrangements of the short arm of chromosome 17 (p13.2) have been found in approximately 63% of cases of ABC [7]. This locus belongs to the ubiquitin-specific protease 6 (USP6), also known as Tre-2. Through promoter swapping, USP6 contributes its entire coding sequence as the 3' portion, and its transcription is substantially enhanced by replaceable 5' partner genes juxtaposed to the untranslated regulatory element of USP6 [16]. As a result, the gene induces the production of matrix metalloproteinase activity via nuclear factor-kB. The most common fusion partner for the USP6 gene is CDH11 (about 30%); however, other genes such as TRAP150 (THRAP3), ZNF9 (CNBP), OMD, COL1A1, RUNX2, PAFAH1B1, CTNNB1, SEC31A, E1F1, FOSL2, STAT3, USP9X, ASAP1, FAT1, SAR1A, TNC, SPARC have been reported [17-19]. Rare cases of an unusually aggressive ABC with soft tissue extension and RUNX::USP6 fusion is also reported [20]. Rearrangement of the USP6 gene can be detected by fluorescence in-situ hybridization or fusion panel analysis such as targeted RNA sequencing.

Rearrangement of the USP6 gene has also been found in other soft tissue neoplasms; some with a limited capacity of bone formation, mimicking sarcomas; however, with limited growth potential and non-aggressive clinical course. These entities include nodular fasciitis, cellular fibroma of tendon sheath, myositis ossificans, and fibro-osseous pseudo tumor of digit. This common finding suggests that these neoplasms might belong to a spectrum of disease processes that can best be referred to as USP6-associated neoplasms [16,21-24].

It is important to differentiate primary ABC from lesions with ABC-like changes. Such changes are more common in giant cell tumors of bone, fibrous dysplasia, chondroblastoma, osteoblastoma, and even osteosarcoma [4].

Radiographic findings often aid in narrowing down the differential diagnoses. As a general rule, any epiphyseal or diaphyseal-based lesion raises the possibility of ABC-like changes more than the primary ABC. For example, a diaphyseal lesion with multiple cysts and fluid-fluid levels indicates the possibility of telangiectatic osteosarcoma. The cystic epiphyseal-based lesions suggest the ABC-like changes in an underlying giant cell tumor of bone or chondroblastoma, depending on the patient’s skeletal maturity.

In cases of giant cell tumor of bone with secondary ABC changes, immunohistochemical stain for H3F3A G34W (or other histone markers) can aid in diagnosis. The mononuclear cells of the giant cell tumor show nuclear immunoreactivity for the histone markers; however, the primary ABC does not demonstrate such a finding.

Distinction from telangiectatic osteosarcoma can be challenging due to some overlapping clinical and radiographic features. Unlike ABC, telangiectatic osteosarcoma shows highly atypical and anaplastic cells within the stroma, frequent atypical mitoses, and sometimes necrosis. Osteoid matrix production is minimal in these lesions. ABC shows frequent rearrangement of the USP6 gene; however, telangiectatic osteosarcoma does not show such findings. There is no specific immunohistochemical stain that aids in the differential diagnosis of these entities.

Central giant cell granuloma involves the gnathic bones and mimics “solid ABC.” It is usually solid with no or minimal cystic components. Cytologic atypia and necrosis are also not common. Unlike ABC, they lack rearrangement of the USP6 gene [25].

Although the overall prognosis of ABC is good, the goal of any treatment modality is to slow down the disease progression, symptom relief, and fixation or prevention of pathologic fracture. En-bloc resection, although produces the least rate of disease recurrence [26,27], is not commonly performed due to an increased rate of functional impairment and morbidity [28]. Curettage with or without bone grafting is more commonly performed especially in anatomic locations amenable to surgical intervention.

Other therapeutic modalities including percutaneous doxycycline injection [29], arterial embolization, steroid or calcitonin injection, bisphosphonates, and RANKL inhibitors have been shown to be effective in the treatment of ABC in special clinical settings [30-35].

Local recurrence is seen in up to 1/3 of the cases, especially within the few months after the initial treatment, however, it is very rare after 2 years. Young age and open growth plates are also associated with an increased risk of local recurrence [36]. Rare cases of ABC with metastatic disease have also been reported [37].

Proper characterization of primary ABC of bone from ABC-like changes in other benign and malignant diseases requires the correlation of radiographic and pathologic findings. In challenging cases, molecular studies to identify the rearrangement of the USP6 gene will aid in diagnosis.