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| Year : 2016 | Volume
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| Issue : 2 | Page : 148-152 |
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| Angiomatoid fibrous histiocytoma: Clinicopathological spectrum of five cases, including EWSR1-CREB1 positive result in a single case |
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Bharat Rekhi, Shraddha Adamane, Kiran Ghodke, Saral Desai, Nirmala A Jambhekar
Department of Surgical Pathology, Tata Memorial Centre, Mumbai, Maharashtra, India
Click here for correspondence address and email
| Date of Web Publication | 9-May-2016 |
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 Abstract | | |
Background: Angiomatoid fibrous histiocytoma (AFH) is an unusual soft tissue tumor (STT), characterized by recurrences, but rarely metastasis. Later, certain molecular signatures have been identified underlying this tumor, which at times, is either underdiagnosed as a benign vascular tumor, or over diagnosed as a high-grade pleomorphic sarcoma, including a malignant fibrous histiocytoma. Materials and Methods: Over a 14-year-period, five diagnosed cases of AFH were analyzed. Results: Five tumors occurred in three males and two females, over a wide age-range (median = 21, mean = 30 years); mostly in the extremities (4) (80%). Microscopically, most tumors were circumscribed, comprising large, blood-filed spaces with surrounding histiocytic cells and a “cuff” of lymphoplasmacytic cells. Three tumors revealed solid growth pattern with polygonal to spindle cells, including myxoid matrix in one of these tumors. On molecular analysis, this tumor exhibited EWS-CREB transcript. Immunohistochemically, various tumors were positive for CD68 (n = 2/2), epithelial membrane antigen (n = 3/4), CD99/MIC2 (n = 2/3), and desmin (n = 1/4). All tumors were surgically excised. On follow-up (n = 2), a single patient, who underwent wide-excision was free-of-disease (24 months), while another patient had a recurrence 4 months post tumor excision. Conclusions: This forms as the first documented series on clinicopathological features of AFH, a rare STT, from our country. Significant clinicopathological features include younger age, extremities as commonest site and histopathological appearance of blood-filled spaces with surrounding “cuff” of histiocytic cells and lymphocytes. Tumors with unusual histopathological tumor patterns require molecular confirmation. Surgical resection remains the treatment mainstay. Keywords: Angiomatoid fibrous histiocytoma, EWSR1-ATF1, EWSR1-CREB1, malignant fibrous histiocytoma
How to cite this article:
Rekhi B, Adamane S, Ghodke K, Desai S, Jambhekar NA. Angiomatoid fibrous histiocytoma: Clinicopathological spectrum of five cases, including EWSR1-CREB1 positive result in a single case. Indian J Pathol Microbiol 2016;59:148-52 |
How to cite this URL:
Rekhi B, Adamane S, Ghodke K, Desai S, Jambhekar NA. Angiomatoid fibrous histiocytoma: Clinicopathological spectrum of five cases, including EWSR1-CREB1 positive result in a single case. Indian J Pathol Microbiol [serial online] 2016 [cited 2023 Oct 2];59:148-52. Available from: https://www.ijpmonline.org/text.asp?2016/59/2/148/182023 |
| Introduction | |  |
Angiomatoid fibrous histiocytoma (AFH), first described by Enzinger,[1] is an uncommon soft tissue tumor, characterized by low malignant potential and rare metastasis. It accounts for 0.3% of all soft tissue sarcomas; commonly occurs in the deep dermis and subcutaneous tissues of extremities; has distinct clinicopathological features and lately, is known to be associated with certain underlying genetic signatures.[2]
AFH was initially considered as a variant of malignant fibrous histiocytoma (MFH); although clinical features, such as younger age of presentation and superficial location were in contrast to MFH, which invariably occurs in the deeper locations and in individuals in seventh to eighth decades of life. Subsequent studies elucidated that it differed substantially in its behavior from other tumors, especially a MFH.[3]
Herein, we present clinicopathological spectrum of five cases of AFH reviewed at a single tertiary cancer referral institute, including molecular results in a single case. This forms the first study of AFH from India, to the best of our knowledge.
| Materials and Methods | | |
After computerized search of medical records from 1st January, 2000, to 31st December, 2014, 14 cases were identified with a diagnosis of either, AFH, or angiomatoid variant of MFH. Conventional hematoxylin and eosin stained along with immunohistochemical (IHC) stained microsections were reviewed by two authors (BR with SA). Subsequently, five cases were included after review, as per established criteria.[2] These included consultation cases of NAJ and BR. Two cases with an unequivocal, diagnosis of AFH were excluded, in view of older slides and paraffin blocks that were discarded (more than 10 years old).
IHC staining was performed using the polymer technique (Dako REAL Envision detection system, Glostrup, Denmark) including peroxidase/3-3-diaminobenzidine tetrahydrochloride. Details of various antibody markers have been enlisted in [Table 1].
A single tumor (case 5) was subjected to molecular analysis by reverse transcriptase–polymerase chain reaction (RT-PCR) for various fusion transcripts, namely EWS-CREB1, EWS-ATF1, EWS-NR4A3, TAF15-NR4A3, ETV6-NTRK3, and FUS-ATF1 at Kitakyushi, Japan.
| Results | | |
Out of five cases, three occurred in males and two in females (M:F = 1.5:1), with age-range of 7–62 years (median = 21, mean = 30). Site-wise, all five tumors were superficially located in the soft tissues of upper extremity (three cases, 60%), followed by lower extremity (one case, 20%) and in cervical/neck region (one case, 20%). Clinically, most patients presented with a painless swelling.
On histopathological review, four out of five tumors were well-circumscribed, predominantly composed of large blood-filled spaces, juxtaposed with cellular areas composed of polygonal to spindle cells arranged in fascicles and whorls. Interspersed were pleomorphic and giant cells in 4/5 (80%) tumors. Mitotic figures ranged from 1–2 to 6–7/hpf, un-associated with atypical forms. Solid tumor pattern was noted in three tumors, out of which two were almost solid, including one tumor that displayed cord-like arrangement of cells in a focally myxoid matrix [Figure 1]a,[Figure 1]b,[Figure 1]c and [Figure 2]a,[Figure 2]b,[Figure 2]c. While a single tumor displayed fibrinoid necrosis, none of the tumors showed the presence of coagulative tumor necrosis. | Figure 1: Angiomatoid fibrous histiocytoma. Microscopic findings (a) Case 3. Large dilated blood-filled spaces lined by cellular areas, blending with “cuff” of lymphocytes an plasma cells (H and E, ×40). (b) Areas displaying tumor nodularity and circumscription with compact cell arrangement (H and E, ×40). (c) Tumor cells with vesicular nuclei, including pleomorphic cells admixed with inflammatory cells. Inset: occasional mitotic figure (H and E, ×400). (d). Immunohistochemistry: Diffuse CD68 positivity (Diaminobenzidine, ×400). (e) Focal Epithelial membrane antigen positivity (Diaminobenzidine, ×400)
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 | Figure 2: Case 5. (a) Tumor with a pale center comprising solid tumor pattern, surrounded by the cuff of lymphocytes an plasma cells (H and E, ×40). (b) Tumor cells within an amphophilic stroma with dense lymphocytes an plasma cells in proximity (H and E, ×200). (c) Polygonal to short spindle cells arranged in a myxoid matrix. (d) Immunohistochemical staining displaying diffuse CD68 positivity within tumor cells (Diaminobenzidine, ×400). (e) Focal epithelial membrane antigen positivity within tumor cells (Diaminobenzidine, ×400)
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A significant proportion of chronic inflammatory cells comprising lymphocytes and plasma cells were seen in almost all tumors. In all five tumors, lymphoid follicles with secondary germinal center formation were noted at the periphery, simulating the appearance of a lymph node. The inflammatory infiltrate further merged with the adjoining fibro collagenous tissue of the lesion which appeared to form the pseudocapsule for the lesion. Two tumors revealed infiltration into adjacent skeletal muscles.
IHC stained sections were available in all five tumors. Epithelial membrane antigen (EMA) was positively expressed in 3/4 tumors; CD68 in 2/2; MIC2/CD99 in 2/3 tumors and desmin in 1/4 tumors [Figure 1]d and [Figure 1]e and [Figure 2]d and [Figure 2]e, [Table 2].
Further on molecular testing in case 5, the tumor was found to be positive for EWS-CREB1[Figure 3]. | Figure 3: Reverse transcriptase–polymerase chain reaction results in case 5 displaying positive band for EWSR1-CREB1 transcript
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Among five patients, a single patient, who underwent a wide-excision after the primary excision was free-of-disease (24 months). Another patient had a recurrence of a 3 cm-sized tumor at the same site 4 months after tumor excision and was planned for re-excision.
| Discussion | | |
This is the first study on clinicopathological spectrum of AFH from our country describing a wide age-range, including median age of 21 years, slight male predilection; extremities as common sites of occurrence, especially ''sites of normal lymphoid tissue'' and swelling as the commonest symptom, in congruence with other documented studies from the West.[3],[4],[5] Pyrexia, anemia, weight loss, and malaise are other known symptoms associated with this tumor.[1],[4] Other documented extra-somatic soft tissue locations of AFH, include lung, mediastinum, vulva, retroperitoneum, ovary, brain, and bone.[6],[7],[8] Tumor size varies from 2 to 4 cm, however large-sized AFHs been described.[2] Most tumors behave in a relatively indolent manner, with a recurrence rate of 15% and a metastatic rate of nearly 1%.[3],[4],[5]
On gross examination, AFH appears as a firm and circumscribed tumor, which on cut surface shows blood-filled cystic areas in most tumors. This transcends into similar histopathological features, including a fairly well-circumscribed tumor with hemorrhagic cystic spaces, as the most common feature, also noted in our series.[1],[2],[3],[4],[5] However, the presence of the blood-filled cysts cannot be explained in these tumors as the patients neither have defects in their coagulation system nor have thrombocytopenia.[9] The striking histopathological clues towards diagnosing a AFH include peritumoral “cuff” of lymphocytes an plasma cells, multinodular growth pattern and dendritic cell tumor-like morphology (tumor cells with eosinophilic cytoplasm and indistinct cell borders), as noted in almost all cases of the present series.[2],[3],[4],[5] Uncommonly, the solid or cellular variants of AFH show more cellular areas of fibrohistiocytic cells than the vascular spaces, as noted in our two cases. Occasional presence of giant cells, nuclear pleomorphism and increased mitotic activity, as observed in some cases are well-documented features.[3] Another documented subtype is round cell predominant AFH.[5]
Immunohistochemically, there is no single specific marker for diagnosis of AFH. Nonetheless, these tumors express the variable percentage of histiocytic antibody marker such as CD68, myogenic antibody marker such as desmin, an epithelial marker such as EMA as well as CD99/MIC2, as similarly noted in our study.[2],[3],[4],[5],[10],[11],[12]
Exact histogenesis of AFH is still debatable, although the early postulation from ultrastructural studies that this tumor was of endothelial derivation was disproved as a result of consistent IHC negativity for endothelial markers.[10] Despite frequent CD68 expression might suggest histiocytic differentiation, this marker can be nonspecific and analysis of other histiocytic antigens such as CD163 has been negative.[11] The current hypothesis, based on findings of desmin-positive cells within the lymphoid proliferation is suggestive of a myoid or myofibroblastic lineage.[2],[4],[5] Some authors have suggested the possibility of origin from fibroblastic reticulum cells found within the stroma of normal lymph nodes, with desmin-positivity partially supportive of the myoid differentiation.[5] Furthermore, variable percentage positivity for other smooth muscle markers such as muscle-specific and smooth muscle actin, heavy-caldesmon, calponin, and h-caldesmon in AFH has been indicative of smooth muscle origin, none of the skeletal muscle specific markers have been found to be positive, so far.[2],[4],[5],[11]
AFH can be confused with various benign as well as malignant entities, as a result of its rarity and limited biopsy samples that could result in a lack of characteristic histopathological features. While its differentiation from the benign entity is essential to ensure an adequate resection, in view of its potential for the recurrences; its distinction from a high-grade sarcoma is important to avoid radical resection and adjuvant chemotherapy. Among benign tumors, sclerosing hemangioma forms an important differential diagnosis Presence of the endothelial cell lined vascular channels, intracytoplasmic luminae, along with IHC expression of vascular markers, namely CD31, CD34 and Fli-1 distinguishes this tumor from AFH. Conversely, large cyst-like hemorrhagic spaces lined by histiocyte-like cells, noted in AFH, are uncommonly identified in a vascular neoplasm. Nodular Kaposi's sarcoma (KS) forms as another differential, as was seen during this study, wherein one of the cases of an HIV-positive intranodal KS was misdiagnosed as an AFH. Predominant spindle cell or “slit-cell” pattern in KS with positive expression of vascular IHC markers along with HHV8 are not seen in AFH. These features also help in differentiating AFH from benign or malignant hemangiopericytoma (HPC). Moreover, KS and HPC commonly occur in the older individuals, in contrast to AFH that has a predilection for relatively younger individuals.
Lack of tumor necrosis, atypical mitotic figures along with the infrequent presence of tumor giant cells is helpful in differentiating AFH from MFH/pleomorphic sarcoma-not otherwise specified. Round cell variant of AFH can be misdiagnosed as Ewing sarcoma (ES)/primitive neuroectodermal tumor, especially when MIC2/CD99 is expressed by both tumors. Lack of pseudorosettes, distinct histopathological features, and absent staining for neural markers favor AFH, over ES.
Follicular dendritic cell sarcoma, another differential diagnosis of AFH, is characterized by similar looking nuclei along with positive IHC expression of CD23, CD21, and CD35. At times, AFH can be mistaken for the granulomas especially with the solid variant displaying the diffuse sheets of histiocyte-like cells. Other fibrohistiocytic tumors, namely aneurysmal benign fibrous histiocytoma or diffuse type of giant cell tumor mimic AFH. Large blood-filled cystic spaces do not favor a fibrohistiocytic tumor. Metastasis of a fibrohistiocytic tumor to lymph node may enter as another differential, as was noted in one of our cases. The absence of subcapsular and medullary sinuses helped in differentiating AFH from nodal metastasis, in that case, which was further confirmed with molecular analysis.
Molecular/cytogenetic studies have unravelled specific translocations underlying AFHs, namely t (12:16) (q13:p11), leading to FUS/ATF1; t (12:22) (q13:q12) leading to EWSR1/ATF1 and t (2:22) (q34:q12), leading to EWSR1-CREB1 fusion transcript.[13],[14],[15] EWSR1-CREB1 transcript was detected in the fifth case of the present study, where this trascript was tested by RT-PCR. The ATF1 gene encodes a member of the CREB-ATF basic leucine-zipper family of transcription factors. Both FUS and EWSR1 encode highly conserved members of the TET family of RNA-binding proteins and may serve as alternative 5-fusion partners with ATF1.
It is noteworthy that FUS and EWSR1have played similar corresponding roles in other sarcomas.[16],[17] t (12: 16) (q13:p11) translocation is also seen in a myxoid liposarcoma (LPS), that is, the translocation is unique at the molecular, but not at karyotypic level. In a myxoid LPS, this translocation generates a fusion of the DDIT3 (CHOP) and FUSgenes on 12q13 and 16p11, respectively, resulting in DDIT3/FUS chimeric protein that is considered as diagnostic for myxoid LPS.[13]
Likewise, the EWSR1/ATF1 translocation is also found in clear cell sarcoma, which is an aggressive soft tissue sarcoma, characterized by melanocytic differentiation. Similar to AF, it mainly affects young adults, but is clinicopathologically and immunohistochemically distinct from AFH. The EWSR1-ATF1 chimera appears to represent a rare example of a fusion gene that can be associated with different tumor types.[16] Similarly, EWSR1-CREB1 is also identified in gastrointestinal clear cell sarcoma.[15] In their study of 14 cases of AFH, tested for EWSR1, CREB1, and ATF1 rearrangements, Rossi et al.[15] observed EWSR1 and CREB1 rearrangement in 13 cases, while EWSR1 and ATF1 rearrangement in the remaining case, therefore achieving 100% sensitivity with molecular testing in AFH. At the same time, their study reinforced the concept of chromosomal infidelity between AFH and clear cell sarcoma, including of gastrointestinal tract. Therefore, molecular test results should be interpreted in a clinicopathological context.
Therapeutically, most tumors in this study were resected, as observed in earlier series.[3],[18] In a large series, Costa and Weiss [3] observed recurrences in 12% cases a metastasis in 5% cases. They observed that development of both local and distant metastases correlated with invasion into the deep fascia.
The limitations of this study were a lack of results of a uniform panel of IHC markers in all cases. This is because there is no single specific marker known for diagnosis of AFH. The other limitation was clinical follow-up as most cases were referrals from other centers. Nonetheless; a single patient with wide-resection was free-of-disease, while another with incomplete resection developed recurrences.
To summarize, this first study on AFH from our country is presented to share its key histopathological features, including molecular events underlying this tumor that is known for recurrences and rare metastasis. A timely wide resection seems the treatment mainstay. Rarely occurring unresectable and metastatic tumors are candidates for adjuvant chemotherapy.[19] Furthermore, while underlying molecular results are highly sensitive, these are not equally specific for the diagnosis of AFH and should be interpreted in conjunction with clinicopathological features.
Acknowledgment
We would like to thank Dr. Hiroshi Hashimoto, Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan for his valuable opinion in case 5 and also for the molecular results.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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Correspondence Address:
Bharat Rekhi
Department of Pathology, 8th Floor, Room No. 818, Annex Building, Tata Memorial Hospital, Dr. E.B. Road, Parel, Mumbai - 400 012, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0377-4929.182023
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2] |
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