Angiomatoid fibrous histiocytoma: a series of seven cases including genetically confirmed aggressive cases and a literature review

Classified as an intermediate tumor using the WHO classification, AFH rarely metastasizes [2]. It generally follows an excellent clinical course overall. It frequently occurs in children and young adults in soft tissues, forming a well-circumscribed subcutaneous nodule on the extremities, head, neck, and trunk. No well-organized clinical reports exist for AFH because it is a very rare soft tissue tumor.

Although patients with AFH typically present with a subcutaneous soft tissue lump, Costa and Weiss et al. reported that 18% of tumors invaded deep structures such as skeletal muscle [3]. In our series, three cases (43%) were in deep lesions. According to previous reports, pain and tenderness were rarely encountered in AFH patients [1, 6, 14]. In our series, only one case (case 3) had a painful mass. In addition, AFH often occurs in children and young adults [1, 2]. However, three of seven patients examined in the present study were older than 30 years.

On MRI examination, AFH shows homogeneously hypointense lesions on the T1 WI and heterogeneously hyperintense lesions on the T2 WI [12]. The pattern of gadolinium enhancement is a variegated internal and nodular peripheral appearance. In addition, some groups reported that AFH shows cystic areas, pseudocapsules, hemosiderin, and fluid–fluid levels on MRI [7‐13]. Martinez et al. reported the double rim sign and invasive pattern as novel MRI findings for AFH [15]. The double rim sign refers to the presence of a rim of high signal intensity (RHS) and an adjacent rim of low signal intensity (RLS), which can be observed on both T2-weighted and post-contrast images. The invasive pattern presents as irregular infiltrating peritumoral strings of high signal intensity on T2-weighted and post-contrast images. We believe that these signs were present in the pseudocapsule, peritumoral edema, and enhancement of our series. However, these two typical views were observed only in two cases (cases 3 and 5). Consequently, the MRI findings of AFH are nonspecific. Because of its radiological features and indolent clinical behavior [14], it is often mistaken for a benign condition such as a hematoma or hemangioma, potentially leading to inappropriate treatments. Indeed, in our series, three cases were misdiagnosed from initial MRI findings as a hematoma or hemangioma. Consequently, histopathological examination is extremely important to reach a definitive diagnosis.

The characteristic histological features of AFH have been well described [2]. These features include the following: (i) multinodular growth of myoid spindled or histiocytoid cells with a distinctive syncytial appearance, (ii) pseudoangiomatous spaces filled with blood and surrounded by tumor cells, (iii) a thick fibrous pseudocapsule with prominent hemosiderin deposition, and (iv) peritumoral lymphoplasmacytic cuffing with occasional germinal center formation. However, AFH can display a wide morphological spectrum. One or more of the above-described histological findings might be lacking. Nevertheless, multinodular growth of myoid spindle cells is consistent. Devoting attention to this pattern and cytology is crucial for accurate diagnosis. Unusual morphological features that have been reported in a small number of AFHs include clear cells, small cells with scanty cytoplasm resembling Ewing’s sarcoma, and rhabdomyoblast-like cells [2, 16, 17]. In addition, a myxoid variant has been established recently in which the tumors exhibit reticular growth in a prominent myxoid background. The diagnosis of myxoid AFH can be particularly challenging. Differential diagnosis includes other myxoid tumors such as low-grade fibromyxoid sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma [18]. Although there are no entirely specific immunohistochemical markers for AFH, approximately half of the tumors express desmin. Epithelial membrane antigen expression is also characteristic of AFHs. In addition, AFHs can be uncommonly positive for other myoid markers such as smooth muscle actin, calponin, or, rarely, h-caldesmon, but skeletal muscle markers such as myogenin or MyoD1 are consistently negative [19]. In our series, aside from two cases (cases 1 and 7), none were diagnosed correctly as AFH from the initial biopsies. Cases 2 and 6 were misdiagnosed even after excision.

Recent reports have noted that molecular analyses are useful ancillary diagnostic techniques for AFH. These analyses include fluorescence in situ hybridization (FISH) to detect the rearrangement of EWSR1 or FUS and reverse transcription-polymerase chain reaction (RT-PCR) to elucidate EWSR1-CREB1, EWSR1-ATF1, or FUS-ATF1 fusion transcripts [16, 17, 20]. Tanas et al. reported that 76% of assessed AFH were shown by FISH to harbor EWSR1 rearrangement [20]. Thway et al. showed that both FISH and RT-PCR are equally reliable for facilitating an AFH diagnosis because one technique can identify the cases that the other method misses [21]. The detection of EWSR1 rearrangement by FISH was indeed helpful for reaching the correct diagnosis in our series, including five cases (cases 2–6) to which incorrect labeling was assigned initially. In addition, CREB1 gene rearrangement further supported the diagnoses in 2 cases (cases 3 and 6) that showed unexpected aggressive courses. We believe that molecular methods are sometimes necessary for the diagnosis of AFH.

A summary and comparison of the clinical outcomes of AFH cases described in earlier reports are presented in Table 4. Although some groups reported a favorable prognosis of AFH after treatment [3, 22, 23], Enzinger et al. reported that 63% and 21% of patients had local recurrence and metastasis, respectively, and that 12% of patients had died of the disease. In a study by Pettinato et al. [22], the prognoses were not good: recurrence occurred in 25% of cases, metastasis occurred in 5% of cases, and death occurred in 5% of cases. However, some reports published before the establishment of molecular analyses might have included malignant neoplasms other than AFH. In our series, five patients remained alive and well without recurrence or metastasis after resection. However, two patients (29%) had tumor recurrence and metastasis, one of whom died from disease progression. Notably, the diagnosis of AFH in both of these aggressive cases was confirmed by FISH on a molecular level for the presence of rearrangements of both EWSR1 and CREB1. Tamas et al. reported that the influence of the EWSR1-CREB1 fusion gene on prognosis was not clear [24]. In the AFH cases in which the EWSR1-CREB1 fusion gene was detected, only one recurrence case was reported [16]; there were no reported deaths. Case 6 may be the first fatal case in which EWSR1-CREB1 was detected. Therefore, the clinical outcome of our cases was unexpectedly worse than that of others described in the literature. Additionally, we administered systemic chemotherapy in case 6, but it was ineffective. Our results suggest that AFH patients may follow an unfortunate course that can rarely be predicted.

Costa et al. reported that an irregular tumor border as well as a head and neck location were associated with local recurrence, and the depth of the tumor was correlated with subsequent local and distant metastasis [3]. Furthermore, they showed that the mitotic activity, extreme pleomorphism, inflammatory response, tumor size, patient age, and adjuvant therapy were not correlated with the clinical behavior. In other studies, the degree of mitotic activity and atypia showed no correlation with the risk of recurrence. There have been no reports showing that genetic factors or immunohistochemical profiles are related to clinical behavior. In our small number of cases, we detected no definite correlation between clinical characteristics and prognosis. Nevertheless, we did note several features that might be relevant in the two cases that showed an aggressive course (cases 3 and 6). Specifically, the primary tumor in case 3 was the only one in our series that presented as a painful mass, and it exhibited an unusual small round cell morphology with marked mitotic activity, although its recurrence showed the classic spindle cell histology of AFH. Case 6 manifested as a large mass in a deep location, and its recurrence demonstrated focally increased nuclear atypia and pleomorphism compared to the classic morphology of primary tumors. Interestingly, these pleomorphic tumor cells harbored an increased (up to 12 copies) number of rearranged EWSR1 genes in contrast to a signal copy in non-pleomorphic areas. We suspect that it may be worthwhile to investigate these features to see if they predict local recurrence and distant metastasis.