Angiomatoid Fibrous Histiocytoma: A Series of Three Cases

Angiomatoid fibrous histiocytoma (AFH) is a rare, slow-growing soft tissue tumor with an intermediate biologic potential and uncertain line of differentiation, and minimal metastatic potential. AFH may mimic both the clinical, histological, and radiological findings of several tumors; therefore, it is frequently misdiagnosed. Three cases of AFH were included in this study. A six-year-old male and two females with an age of 12 and 17 years are presented. The primary locations were in the right shoulder (case 1), left medial proximal thigh (case 2), and left lateral knee (case 3). Two cases (cases 2&3) were presented with a painful mass. In the three patients, the masses were firm, mobile, and not attached to the skin. Magnetic resonance imaging (MRI) was done, illustrating unspecific findings to reach a diagnosis. Needle biopsies were performed in all patient, and the diagnosis of AFH was reached. All three patients underwent wide surgical excision of the tumor. Patients were followed up routinely every three to four months with imaging studies to rule out recurrence and metastasis, for a period of 15 months (case 1), 26 months (case 2), and 19 months (case 3), which all resulted negatively.


Introduction
Angiomatoid fibrous histiocytoma (AFH) is a rare, slow-growing soft tissue tumor with an intermediate biologic potential and uncertain line of differentiation, and minimal metastatic potential [1,2,3]. AFH may mimic both the clinical, histological, and radiological findings of several tumors; therefore, it is frequently misdiagnosed [3]. The main presentation is painless soft tissue mass, accompanied by systemic symptoms, like anemia, weight loss, and fever, although atypical presentations have been reported [4].
AFH can also present as a slowly growing, superficial nodular mass that is rarely causing pain or tenderness, a matter that makes it misdiagnosed as a hematoma or a hemangioma [5]. It could also be presented by symptoms related to the anatomic site [6]. Molecular studies play a valuable role in confirming the diagnosis of AFH in adjunct to clinical and pathological findings, where the rearrangement of Ewing sarcoma breakpoint region one gene (EWSR1) being a positive finding in (83%) of the cases [4]. Furthermore, AFH is commonly occurring in the extremities of patients in their first three decades of life, affecting 1 in 100,000 of the population, with slight male predominance [1,7 ]. The variable patterns of AFH could lead to diagnostic difficulties and missing diagnoses if the molecular investigation was not done [8]. Many cases have been reported in the literature; nevertheless, none of them in Saudi Arabia, to the best of our knowledge. We have compiled a series of three cases of AFH at our institution, with two presenting with a painful mass. Herein we are discussing the clinical feature, radiological, histopathological, and cytogenic findings.

Case Presentation
The presented three cases were a six-year-old male (case 1) and two female patients with an age of 12 (case 2) and 17 (case 3) years old. The primary locations were in the shoulder (case 1), medial proximal thigh (case 2), and lateral knee (case 3). Two cases (cases 2&3) were presented with a painful mass. In the three patients, the masses were firm, mobile, not attached to the skin, and no skin discolorations except bluish discoloration in one patient (case 3). The approximate sizes of the tumors were 3x3 cm (case 1) and 4x5 cm (case 2&3). All patients had a full range of motion and no other relevant symptoms.
Magnetic resonance imaging (MRI) for one patient (case 1) showed multi-septate cystic lesion, fluid-fluid levels, heterogeneous intermediate to low signal intensity in T1-weighted image (T1WI), and heterogeneous high signal intensity in T2-weighted/short T1 inversion recovery (STIR) with the hemorrhagic component. It shows minimal if any enhancement post-gadolinium administration. The differential was a periostealrelated aneurysmal bone cyst. Multiple enhancing right axillary lymph nodes, the largest measures 1.6x0.9 cm, worrisome for metastasis. MRI was repeated one month later, which shows a significant interval increase in size measuring 3.6x4.5x4.4 cm in anterior-posterior (AP), transverse, and cubic centimeter (CC) dimensions compared to 3.3x2.9x3.1 cm previously ( Figure 1). The second patient (case 2) showed oval shape soft tissue mass with lobulated margin, cystic degeneration with multiple areas of fluid-fluid levels suggestive of intra lesion hemorrhagic components, hypo-intense signal intensity in T1, and heterogeneous hyper-intense signal intensity in T2. After administration of IV contrast, enhanced superior tail around the lesion and enhancement of the soft tissue component within the lesion is seen with no enhancement of cystic components differential diagnosis were: nerve sheath tumors such as schwannoma or soft tissue sarcoma such as synovial sarcoma. Multiple enhanced lymph nodes were seen in the left inguinal region, suggestive of metastasis ( Figure 2). The third patient (case 3) came with an outside MRI report that was suggestive of synovial sarcoma ( Figure 3). All patients showed no bone involvement. No case was initially diagnosed as AFH. CT scan staging showed no metastasis in all three patients, and Triphasic technetium 99 m methyl diphosphonate (MDP) bone scan was done in one patient (case 2) where the tumor showed hyperemia in both flow and blood pool phases ( Figure 4). The rest of the study demonstrates physiologic radiotracer distribution for age.   All patients underwent surgical excision of the tumor with negative margins, and there were no immediate complications except for one patient who required a skin graft (case 3). Surgical excision specimen subjected to histopathological diagnosis confirming the needle biopsy results. Patients were followed up routinely every three to four months, for the last fifteen (case 1), twenty-six (case 2), and nineteen (case 3) months, with imaging studies to rule out recurrence and metastasis, which were negative. All patients have a full range of motion with no complaints. All cases were summarized in Table 1

Discussion
Angiomatoid Fibrous Histiocytoma (AFH) accounts for 0.3% of all soft tissue tumors. It is classified by the World Health Organization (WHO) under the category of tumors of uncertain differentiation [7], after being considered a malignant tumor in the past; due to the infrequent malignant behavior [9,10]. AFH is rarely metastasizing with a reported rate of less than 1% and a very low mortality rate [7]. Nevertheless, there is local recurrence in 2-12% of cases [7]. Typically, AFH is presenting as a painless mass in the cutis or subcutis, some patients could present with a paraneoplastic effect like fever, malaise, weight loss, or anemia, and it is usually located in the extremities [10]; this disagrees with what was found in case 2&3, who presented with a painful mass in the medial proximal thigh and lateral knee. It was found the children and young adults are the most common age group to be affected [11]. However, AFH can present in newborns and even elderlies [11].
Diagnosis of AFH is difficult because of the variability of differential diagnosis that includes: aneurysmal bone cysts, schwannoma, soft tissue sarcomas such as synovial sarcoma based on our radiological reports [12]. Other differential diagnoses are hematoma and hemangioma [12]. Radiological modalities in AFH are not specific and would not lead to a specific diagnosis mimicking both aggressive and more benign masses. Colangeli et al. [12] reported that MRI shows cystic areas with an enhancing fibrous pseudo capsule and internal blood-filled foci, as we saw in our cases.
To reach the diagnosis, histopathology is not sufficient by itself. Histopathological features are well summarized as multinodular growth of myoid spindle or histiocytoid cells with a distinctive syncytial appearance, pseudoangiomatous spaces filled with blood and surrounded by tumor cells, a thick fibrous pseudocapsule with prominent hemosiderin deposition, and peritumoral lymphoplasmacytic cuffing with occasional germinal center formation [2].
There are no reliable histopathological parameters that predict behavior, and both primary AFH and metastatic AFH are frequently morphologically typical, including the genetically documented case of metastatic AFH [13]. EWSR1 gene rearrangements are associated with a variety of soft tissue neoplasms. This gene can fuse with different partner genes leading to the formation of histologically identical neoplasms. At the same time, it can also fuse with the same genes to cause morphologically and behaviorally different tumors [14].
About half of AFH tumors have desmin expression and sometimes exhibit expression of other markers of myoid differentiation as smooth muscle actin, calponin, and rarely h-caldesmon [15]. In this case series, it was positive for desmin, SMA, S100 protein and negative for EMA in one case, and totally the opposite in the other one, which was positive anti-EMA, and being negative for SMA, S100 protein, AE1/AE3, CD34, and desmin.
In AFH cases, a comprehensive approach by imaging, histopathology, immunohistochemistry, and genetic analysis must be followed to diagnose and differentiate AFH from other soft tissue masses to be properly treated and followed up. Reaching the correct diagnosis of AFH comes with a great value; unfortunately, most presentations are atypical, and as a result, it is frequently misdiagnosed, either for more aggressive tumors like myxoid liposarcoma, metastatic melanoma, Ewing's sarcoma, myxofibrosarcoma, and synovial sarcoma, or benign tumors like hematoma, hemangioma, lipoma, nerve sheath tumor, and vascular anomalies and other wide differentials depending on the age group [6]. This misinterpretation leads to either over managing and subjecting the patient to unnecessary procedures or under managing the patient and ignoring the risk of recurrence and metastasis, and leading to unfavorable evens.

Conclusions
The accurate diagnosis of AFH is very important to avoid the risk of metastasis and death from improper treatment. Immunohistochemical studies and molecular confirmation of a positive EWSR1 rearrangement using FISH for AFH are very important for correct diagnosis. This is the first report of three AFH cases in the Kingdom of Saudi Arabia to the best of our knowledge. One was a six-year-old male, and the others were two females of 12 and 17 years.

Additional Information
Disclosures