Document Detail

Subcutaneous angiomatoid fibrous histiocytoma mimicking metastatic melanoma.
Jump to Full Text
MedLine Citation:
PMID:  23320232     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Angiomatoid fibrous histiocytoma is an uncommon soft-tissue tumor of intermediate malignancy that is often misdiagnosed initially. As there is not one immunohistochemical marker that consequently stains positive or negative for angiomatoid fibrous histiocytoma, molecular diagnostics are becoming more widely used. So far three translocations have been reported to arise in angiomatoid fibrous histiocytoma: FUS-ATF1, EWSR1-CREB1, or EWSR1-ATF1. We present a case of angiomatoid fibrous histiocytoma on the upper arm of a 40-year-old female, which was initially misdiagnosed as metastatic melanoma in a lymph node. Revision of the pathology revealed an angiomatoid fibrous histiocytoma, which was later confirmed by a EWSR1-CREB1 translocation with molecular diagnostics. Furthermore, we review the relevant literature and provide an overview of all available case reports in the past ten years. This case report illustrates the importance for pathologists of knowing the typical pathology features of AFH and integrating immunohistochemical and molecular findings in order to prevent overdiagnosis of lymph node metastasis of a malignancy.
E Sparreboom; C Wetzels; M Verdijk; S Mulder; W Blokx
Publication Detail:
Type:  Journal Article     Date:  2012-12-20
Journal Detail:
Title:  Case reports in pathology     Volume:  2012     ISSN:  2090-679X     ISO Abbreviation:  Case Rep Pathol     Publication Date:  2012  
Date Detail:
Created Date:  2013-01-15     Completed Date:  2013-01-16     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  101576609     Medline TA:  Case Rep Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  291623     Citation Subset:  -    
Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9100, 6500 HB Nijmegen, The Netherlands.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Case Report Pathol
Journal ID (iso-abbrev): Case Report Pathol
Journal ID (publisher-id): CRIM.PATHOLOGY
ISSN: 2090-6781
ISSN: 2090-679X
Publisher: Hindawi Publishing Corporation
Article Information
Download PDF
Copyright © 2012 E. Sparreboom et al.
Received Day: 14 Month: 10 Year: 2012
Accepted Day: 6 Month: 11 Year: 2012
Print publication date: Year: 2012
Electronic publication date: Day: 20 Month: 12 Year: 2012
Volume: 2012E-location ID: 291623
PubMed Id: 23320232
ID: 3539338
DOI: 10.1155/2012/291623

Subcutaneous Angiomatoid Fibrous Histiocytoma Mimicking Metastatic Melanoma
E. Sparreboom1*
C. Wetzels2
M. Verdijk1
S. Mulder3
W. Blokx1
1Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9100, 6500 HB Nijmegen, The Netherlands
2Department of Pathology, Maxima Medical Centre, 5500 MB Veldhoven, The Netherlands
3Department of Oncology, Radboud University Nijmegen Medical Centre, P.O. Box 9100, 6500 HB Nijmegen, The Netherlands
Correspondence: *E. Sparreboom:
[other] Academic Editors: K. Aozasa, D. Miliaras, and D. Vlachodimitropoulos

1. Introduction

Angiomatoid fibrous histiocytoma (AFH) is a rare soft-tissue tumor first described by Enzinger in 1979, occurring most commonly in children and young adults [1]. It is classified by the World Health Organization as a fibrohistiocytic tumor of intermediate malignancy [2], with local recurrence rates of 11% and metastatic disease in 1% [3]. AFH develops most frequently on the extremities (65%), followed by the trunk (28%) and head and neck (7%) [4], and is clinically often thought to represent lymphadenopathy, cyst, hemangioma, or Kaposi or Ewing sarcoma [57]. Four main histological features usually seen in AFH are a fibrous pseudocapsule, a round or spindle fibrohistiocytic cell proliferation, a pseudoangiomatous pattern, and a plasmalymphocytic infiltrate [5, 8]. The pathological analysis may, however, be difficult as the tumor may mimic lymph node metastasis of another round or spindle cell malignancy, and specific immunohistochemical stains that provide a conclusive diagnosis are lacking [9]. The use of molecular diagnostics can be helpful in establishing a diagnosis in these cases.

We present the case of a 40-year-old woman whose AFH was initially diagnosed as a lesion suspicious for melanoma metastasis. No primary tumor could be discovered after thorough evaluation by other specialists, hence the pathology of the tumor was revised. The final diagnosis was established by means of immunohistochemistry and demonstration of a specific translocation, EWSR1-CREB1 which is described in AFH.

2. Case Report

A 40-year-old obese Caucasian woman with no relevant medical history presented at another institution with a fast growing, asymptomatic tumor of the left upper arm that had appeared within several weeks. She was otherwise healthy and had no physical complaints, especially no loss of appetite, weight loss, or night sweats. She had quit smoking 5 years ago and did not use any medication.

On clinical examination she had a normal blood pressure and pulse. There was a small, fixed, and nontender subcutaneous tumor on the left upper arm of approximately 2.0 cm in diameter. Inspection of the rest of the body revealed no other suspicious lesions or lymph nodes. Differential diagnosis of the tumor included lipoma, cyst, venous malformation, or lymph node malignancy upon which the lesion was surgically removed.

A gray tan nodule measuring 1.2 cm was excised from the subcutaneous fat of the patients' left upper arm. Pathology revealed a radically excised structure resembling a lymph node in which a tumoral process was seen, consisting of a diffuse proliferation of atypical spindle cells. The atypia was specified by undefined cell borders, an amphophilic cytoplasm, large polygonal nuclei and several in part atypical mitoses (Figure 1(d)). Complementary immunohistochemical stains were negative for HMB-45, KL1, cytokeratin AE1/3, and SMa. There was focal positivity for S100 and Melan A (Figure 2(a)) leading to a presumptive diagnosis elsewhere of a melanoma metastasis.

Further clinical investigation of the patient by a dermatologist, ophthalmologist, gynecologist, and surgeon revealed no lesions suspect for the primary tumor. A CT chest and abdomen and PET CT scan also showed no suspect lesions.

Due to uncertainty about the diagnosis and prognosis of the patient, she was referred to the Radboud University Nijmegen Medical Centre (RUNMC) for a second opinion, at which the pathology of the tumor was revised. We confirmed the signs of cellular atypia as described elsewhere, within a spindle cell proliferation with a nodular texture, covered by normal dermis and epidermis without an intraepidermal melanocytic proliferation. The tumor nodules were partially surrounded by fibrous septa and densely vascularized by a capillary network (Figures 1(a) and 1(c)). A dense and extensive lymphatic infiltrate with no evident subcapsular sinus surrounded the spindle cell proliferation (Figure 1(b)).

We considered upon revision the S100 and Melan A staining to be negative in the lesional cells. More immunohistochemical staining, complementary to the previous stains, was performed. The neoplastic cells were positive for CD99 and EMA (Figure 2(b)) and to a lesser extent for CD31. Some capillary vessels stained positive for desmin; however, the tumor cells did not. Other negative stains included CD34, CD30, CD35, Cd10, HHV8, S100, MITF, CD79a, CD20, CD3, CD2, and CD21.

Conclusion of revision of the pathology showed that the tumor, that was initially thought to consist of metastatic melanoma within a lymph node, was in fact a different type of spindle cell tumor surrounded by an extensive lymphatic infiltrate and densely vascularized by capillaries and a few larger vessels. Given the age of the patient and location of the lesion combined with the histopathologic findings, the diagnosis was adjusted into angiomatoid fibrous histiocytoma. Additional molecular research, performed in support of this diagnosis, showed a gene fusion mutation of EWSR1-CREB1 t(2;22)(q33;q12) (Figure 2(c)), while mutations in BRAF and NRAS genes, common in cutaneous melanoma, could not be detected.

3. Discussion

Angiomatoid fibrous histiocytoma is a mesenchymal tumor of intermediate malignancy of unknown differentiation. Although it was originally reported to arise most frequently on the extremities of children and young adults, many case reports found in the literature describe AFHs developing on other sites of the body, such as the mediastinum [4], bone [10], intrapulmonal [11], or intracranial [11]. A complete overview of sites of origin of AFH in available case reports published in the past 10 years can be found in Table 1. In total 18 case reports on AFH were found in the past decade. In addition some case series were reported [5, 9].

Table 1 shows that most AFHs are found in patients in the first 3 decades of life, though patients aged 80 or more with AFH have also been reported [4, 7]. AFH on the upper extremity of a healthy middle-aged woman can therefore be considered a classic presentation of this tumor.

Due to the fact that AFHs are rare, the typical histological features are relatively unknown to pathologists which can lead to an erroneous diagnosis of malignant disease (Table 1). This is most likely due to the typical dense lymphocytic infiltrate surrounding the tumor, suggestive of a tumor metastasis to a lymph node. In one other reported case (case 1, Table 1), as in our case, metastatic melanoma was a differential diagnostic consideration.

In our case the initial diagnosis was metastatic melanoma in a lymph node, due to the dense capsule and the surrounding plasmalymphocytic infiltrate and focal aspecific staining of lesional cells for melanocytic markers [12, 26, 27]. Careful revision eventually revealed the absence of structures normally found in lymph nodes, such as a subcapsular sinus and triggered further research on the origin of the present tumor.

Interpreting immunohistochemical staining results can be complex, as there is not one immunohistochemical marker that consequently stains positive for AFH. As indicated in Table 1, the majority of studies have reported AFHs to stain positive for CD68 [8, 28], desmin, EMA, and vimentin. Within a small percentage of AFHs other muscle markers such as HHF-35 and calponin also stain positive [29]. The AFH in the present case report showed positive staining for CD99 and EMA, though desmin seemed positive only in the surrounding capillary epithelium and CD68 in the intralesional dendrites. Double immunoreactivity for EMA and desmin is reported to be a diagnostic clue for AFH [5].

Nevertheless, immunohistochemistry has a limited role in establishing the diagnosis of AFH. The knowledge of the existence of this rare entity with its typical pathology features is therefore vital in preventing misdiagnosis.

As the molecular genetics of AFH become increasingly understood, genetic testing is utilized more widely to support the diagnosis of this entity. There are three translocations resulting in fusion genes associated with AFH: FUS/ATF (t(12;16)(q13;p11)) [30], EWSR1/ATF1 (t(12;22)(q13;q12)) [23], and EWSR1/CREB1 (t(2;22)(q33;q12)) fusion genes [31]. In available case reports published in the past 10 years, the EWSR1/ATF1 (t(12;22)(q13;q12) fusion was most commonly found (Table 1). In a series of 9 AFH Antonescu et al. reported that EWSR1-CREB1 was the predominant gene fusion in AFH present in 8/9 cases [31]. In our case, the patient was also tested positive for the EWSR1/CREB1 (t(2;22)(q33;q12)) fusion gene, hereby supporting the diagnosis of AFH. The EWSR1-CREB1 translocation is not unique to AFH but also present in clear cell sarcoma of the gastrointestinal tract and soft tissue [32].

In conclusion, AFH is a rare disease that is often misdiagnosed initially. Prognosis is generally good following wide surgical excision, with low potential of local recurrence and metastasis.

Our case report illustrates the importance for pathologists of knowing the typical pathology features of AFH and integrating immunohistochemical and molecular findings in order to prevent overdiagnosis of lymph node metastasis of a malignancy.

One year following excision, our patient is well without signs of local recurrence or metastasis.

1. Enzinger FM. Angiomatoid malignant fibrous histiocytoma. A distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasmCancerYear: 1979446214721572-s2.0-0018692271228836
2. World Health OrganisationHistological typing of soft tissue tumours
3. Costa MJ,Weiss SW. Angiomatoid malignant fibrous histiocytoma: a follow-up study of 108 cases with evaluation of possible histologic predictors of outcomeAmerican Journal of Surgical PathologyYear: 19901412112611322-s2.0-00256444472174650
4. Moura RD,Wang X,Lonzo ML,Erickson-Johnson MR,García JJ,Oliveira AM. Reticular angiomatoid “malignant” fibrous histiocytoma—a case report with cytogenetics and molecular genetic analysesHuman PathologyYear: 201142135913632-s2.0-7995246823221411119
5. Qian X,Hornick JL,Cibas ES,Cin PD,Domanski HA. Angiomatoid fibrous histiocytoma a series of five cytologic cases with literature review and emphasis on diagnostic pitfallsDiagnostic CytopathologyYear: 201140Supplement 2E86E9322045622
6. Martelli L,Collini P,Meazza C,et al. Angiomatoid fibrous histiocytoma in an HIV-positive childJournal of Pediatric Hematology/OncologyYear: 20083032422442-s2.0-4184912313218376290
7. Fanburg-Smith JC,Miettinen M. Angiomatoid “malignant” fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotypeHuman PathologyYear: 19993011133613432-s2.0-003273949810571514
8. Hasegawa T,Seki K,Ono K,Hirohashi S. Angiomatoid (malignant) fibrous histiocytoma: a peculiar low-grade tumor showing immunophenotypic heterogeneity and ultrastructural variationsPathology InternationalYear: 20005097317382-s2.0-003378156111012987
9. Tanas MR,Rubin BP,Montgomery EA,et al. Utility of FISH in the diagnosis of angiomatoid fibrous histiocytoma: a series of 18 casesModern PathologyYear: 201023193972-s2.0-7394910191319801966
10. Mangham DC,Williams A,Lalam RK,Brundler MA,Leahy MG,Cool WP. Angiomatoid fibrous histiocytoma of bone: a calcifying sclerosing variant mimicking osteosarcomaAmerican Journal of Surgical PathologyYear: 20103422792852-s2.0-7564913620520090505
11. Ochalski PG,Edinger JT,Horowitz MB,et al. Intracranial angiomatoid fibrous histiocytoma presenting as recurrent multifocal intraparenchymal hemorrhage: case reportJournal of NeurosurgeryYear: 201011259789822-s2.0-7795201776619731989
12. Mansfield A,Larson B,Stafford SL,Shives TC,Haddock MG,Dingli D. Angiomatoid fibrous histiocytoma in a 25-year-old maleRare TumorsYear: 20102254562-s2.0-77953463968
13. Song JY,Lee SK,Kim SG,Rotaru H,Baciut M,Dinu C. Angiomatoid fibrous histiocytoma on the hard palate: case reportOral and Maxillofacial SurgeryYear: 201116223724221965132
14. Ajlan AM,Sayegh K,Powell T,et al. Angiomatoid fibrous histiocytoma: magnetic resonance imaging appearance in 2 casesJournal of Computer Assisted TomographyYear: 20103457917942-s2.0-7795814101420861788
15. Cernik C,Channaiah D,Trevino J. Angiomatoid fibrous histiocytoma in a six-year-old childPediatric DermatologyYear: 20092656366382-s2.0-7035000477519840338
16. Ren L,Guo SP,Zhou XG,Chan JKC. Angiomatoid fibrous histiocytoma: first report of primary pulmonary originAmerican Journal of Surgical PathologyYear: 20093310157015742-s2.0-7034966145219654501
17. Weinreb I,Rubin BP,Goldblum JR. Pleomorphic angiomatoid fibrous histiocytoma: a case confirmed by fluorescence in situ hybridization analysis for EWSR1 rearrangementJournal of Cutaneous PathologyYear: 20083598558602-s2.0-4934911414218422688
18. Dunham C,Hussong J,Seiff M,Pfeifer J,Perry A. Primary intracerebral angiomatoid fibrous histiocytoma: report of a case with a t(12;22)(q13;q12) causing type 1 fusion of the EWS and ATF-1 genesAmerican Journal of Surgical PathologyYear: 20083234784842-s2.0-4084909288518300800
19. Koletsa T,Hytiroglou P,Semoglou C,Drevelegas A,Karkavelas G. Angiomatoid fibrous histiocytoma with cystic structures of sweat duct originPathology InternationalYear: 20075785135162-s2.0-3444710022117610476
20. Hallor KH,Micci F,Meis-Kindblom JM,et al. Fusion genes in angiomatoid fibrous histiocytomaCancer LettersYear: 200725111581632-s2.0-3424714935017188428
21. Pratibha R,Ahmed S. Angiomatoid variant of fibrous histiocytoma: a case report and review of literatureInternational Journal of Paediatric DentistryYear: 20061653633692-s2.0-3374660926916879335
22. Lai EC,Chung KM,Chiu HF,Lau WY. Angiomatoid fibrous histiocytoma in the neckANZ Journal of SurgeryYear: 2006766, article 5382-s2.0-33744940305
23. Hallor KH,Mertens F,Jin Y,et al. Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytomaGenes Chromosomes and CancerYear: 2005441971022-s2.0-2304445940715884099
24. Hothi D,Brogan PA,Davis E,Ramsay A,Dillon MJ. Polyarteritis nodosa as a presenting feature of angiomatoid fibrous histiocytomaRheumatologyYear: 20044322452462-s2.0-124231951914739468
25. Raddaoui E,Donner LR,Panagopoulos I. Fusion of the FUS and ATF1 genes in a large, deep-seated angiomatoid fibrous histiocytomaDiagnostic Molecular PathologyYear: 20021131571622-s2.0-003670775212218455
26. Billings SD,Folpe AL. Cutaneous and subcutaneous fibrohistiocytic tumors of intermediate malignancy: an updateAmerican Journal of DermatopathologyYear: 20042621411552-s2.0-184256238715024197
27. Weiss S,Goldblum J. Soft Tissue TumorsYear: 2008Elsevier
28. Smith MEF,Costa MJ,Weiss SW. Evaluation of CD68 and other histiocytic antigens in angiomatoid malignant fibrous histiocytomaAmerican Journal of Surgical PathologyYear: 19911587577632-s2.0-00258794941676879
29. Thway K. Angiomatoid fibrous histiocytoma: a review with recent genetic findingsArchives of Pathology and Laboratory MedicineYear: 200813222732772-s2.0-3894917239318251589
30. Waters BL,Panagopoulos I,Allen EF. Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving Bands 12q13 and 16p11Cancer Genetics and CytogeneticsYear: 200012121091162-s2.0-003379180911063792
31. Antonescu CR,Cin PD,Nafa K,et al. EWSRI-CREBI is the predominant gene fusion in angiomatoid fibrous histiocytomaGenes Chromosomes and CancerYear: 20074612105110602-s2.0-3534902304117724745
32. Wang WL,Mayordomo E,Zhang W,et al. Detection and characterization of EWSR1/ATF1 and EWSR1/CREB1 chimeric transcripts in clear cell sarcoma (melanoma of soft parts)Modern PathologyYear: 2009229120112092-s2.0-6954908990519561568

Article Categories:
  • Case Report

Previous Document:  Unusual foreign body of parotid gland presenting as sialolithiasis: case report and literature revie...
Next Document:  Primary uterine cervix schwannoma: a case report and review of the literature.