Bone & Soft Tissue Pathology

Angiomatoid Fibrous Histiocytoma

Alexander Lazar


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Clinical History:
A female age 11 presents with a 5 cm mass on her right medial knee. The lesion was present for at least 7 months and originally had the appearance of a "bruise". The parents report that the patient has experienced significantly reduced appetite and weight loss over the last several months. Fifteen months after the initial complete excision of the knee mass, a second mass (2.5 cm) appeared in the right lower quadrant (pelvis) adjacent to the iliopsoas muscle with radiologic features suggestive of extensive hemorrhage. Multiple CT-guided biopsies revealed only hemorrhagic material. Ultimately a 4.6 cm mass was excised that was primarily hemorrhagic but showed focal areas of spindle cells identical to previous excision. This pelvic mass was regarded as a regional metastasis. The patient currently has no evidence of disease 9 months after this second resection.


Case 1 - Slide 1
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Figure 1
The tumor is cystic and hemorrhagic and surrounded by a lymphoplasmacytic infiltrate and fibrosis, 20x.
Figure 2
The lymphoid infiltrate focally forms germinal centers, 100x.
Figure 3
The eosinophilic spindle cell component shows bland cytomorphology and is arranged in fascicular to slightly storiform pattern, 200x.

Figure 4
Hemorrhage is noted within the bland, eosinophilic spindle cell component, 100x.
Figure 5
Cystic areas filled with eosinophilic proteinaceous fluid are noted, 100x.

Figure 6
The lymphoplasmacytic infiltrate is intimately associated with the spindle cells, 100x.
Figure 7
Hemosiderin deposition is focally prominent, 100x.

Histologic Features:
The sections show a tumor that is cystic, hemorrhagic, rimmed by a lymphohistiocytoc infiltrate and surrounded by a fibrous pseudocapsule. No subcapsular sinus is noted at the inner edge of the pseudocapsule and thus this lesion does not appear to represent a lymph node despite the prominent peripheral lymphoid tissue with germinal center formation. The eosinophilic spindle cell component shows bland cytomorphology and is arrayed in fascicular to slightly storiform pattern. The lymphoplasmacytic infiltrate is intimately associated with the spindle cells. Hemorrhage and hemosiderin deposition is noted within the spindle cell and more lymphoid portions of the tumor. Focally, cystic areas filled with eosinophilic proteinaceous fluid are noted and these lack an endothelial lining as do the hemorrhagic areas.

Ancillary Studies:
Immunohistochemical studies revealed patchy reactivity for epithelial membrane antigen (EMA) and CD68, and weak patchy reactivity for CD99. The neoplastic cells were negative for SMA, desmin, cytokeratins, S100, CD21, CD23, CD35, HHV8, CD31, CD34, Factor VIII and Factor XIIIa. Fluorescence in situ hybridization (FISH) with break-apart probes revealed rearrangement of both the EWSR1 (22q12) and CREB1 (2q33) loci strongly implicating the presence of a reciprocal translocation.

Differential Diagnosis:
On the basis of the histologic images presented, the differential diagnosis would include:
  • Nodular fasciitis

  • Follicular dendritic cell sarcoma/tumor

  • Aneurysmal/angiomatoid benign fibrous histiocytoma

  • Spindle cell hemangioma

  • Kaposi sarcoma

  • Angiomatoid fibrous histiocytoma

Diagnosis:
Angiomatoid Fibrous Histiocytoma (WHO, 2002) (previously "angiomatoid malignant fibrous histiocytoma")

Discussion:
A discussion of the differential diagnosis listed above follows:

Nodular fasciitis:
The spindle cells in the present case are relatively uniform and lack the tissue culture-like features of nodular fasciitis. The lack of smooth muscle actin (SMA) expression also mitigates against this diagnosis.

Follicular dendritic cell sarcoma/tumor (FDCS):
The spindle cells lack the storiform or whirling pattern of FDSC. While lymphocytes are present, they are generally not present as sprinkled, single cells within the spindle cell component. Characteristic immunoreactivity for CD21, CD23 and CD35 is not seen. The lack of S100 staining effectively excludes interdigitating dendritic cell sarcoma/tumor.

Aneurysmal (benign) fibrous histiocytoma (BFH):
Aneurysmal BFH is essentially a relatively cellular BFH with prominent areas of cystic hemorrhage that are not lined by endothelium. [1, 2] This present case is deeper and the spindle cells are more uniform than usually seen in BFH. Furthermore, this case lacks the characteristic entrapping of collagen at the edges seen in BFH. Deep forms of BFH are encountered from time to time [3] and these tumors can be more sharply circumscribed and composed of more uniform cells than their much more common superficial counterparts. [3] Some cases may even adopt a conspicuous storiform pattern. However, the expression of EMA and CD99 argues against BFH and while not entirely specific, this present case lacked significant expression of Factor XIIIa.

Spindle cell hemangioma (SCH):
No convincing vasoformation (particularly of the cavernous type) is noted and the cystic hemorrhagic areas lack an endothelial lining. The cells are less spindled than usually encountered in SCH, the degree of associated lymphocytic infiltrate would be unusual, and there is no evidence of endothelial differentiation by immunohistochemistry (CD34, CD31 and Factor VIII are negative). Finally, SCH often displays areas of more epithelioid cells with prominent vacuolization. [4]

Kaposi sarcoma (KS):
An 11 year-old female child would be an unusual setting for KS and if considered, this case would be suggestive of the nodular stage. Furthermore, this case lacks vasoformative areas and the characteristic, but sometimes elusive, small hyaline globules. Lymphocytes are often present in KS, but the degree seen in this case would be unusual. Finally, there is no evidence of endothelial differentiation by immunohistochemistry (CD34, CD31 and Factor VIII are negative) as is HHV8, which is seen in most cases of KS. [5] Similar reasoning excludes kaposiform hemangioendothelioma, [6] though the HHV8 results are not relevant in this regard.

Angiomatoid fibrous histiocytoma:
Angiomatoid fibrous histiocytoma (AFH) is an uncommon soft tissue neoplasm first described by Enzinger in 1979. [7] It was initially considered a low-grade malignancy but is currently considered as "intermediate, rarely metastasizing" under the 2002 WHO classification. Metastases are rare and usually regional, occurring in about 1% of cases. Local recurrence can be seen in approximately 10% of cases. Death from metastases is exceedingly rare. [8, 9] Thus, the present case is exceptional in this regard even though the metastasis is clearly regional in nature. Given the overall quite favorable prognosis, the 2002 WHO classification recommends the changing the original nomenclature "angiomatoid malignant fibrous histiocytoma" [7] to "angiomatoid fibrous histiocytoma". [10] This "new" nomenclature should not be taken to imply that the line of differentiation in this tumor is now understood. Indeed, the characteristic immunophenotype of EMA, desmin and CD99 is an unusual combination (each seen in up to 50 % of cases), though all three are not seen simultaneously in every case. EMA and desmin also tend to be patchy and non-uniform in their distribution. CD68 and CD99 are present in many cases, but lack specificity. [8, 11] It is also important to recognize that this neoplasm is not a member of the undifferentiated pleomorphic sarcoma / malignant fibrous histiocytoma family of sarcomas [10] nor should its name be confused with the unrelated aneurysmal (benign) fibrous histiocytoma. [1] Often systemic symptoms or findings such as fever, malaise, anorexia and paraproteinemia are associated with this tumor as in the present case. [7, 8, 9] Cases have been described at all ages, but the majority of cases occur in younger patients, usually below the age of 30. AFH has a propensity to occur in the extremities more often than the trunk and is often seen in areas rich in lymphoid tissue such as the popliteal or decubital fossa and the neck. While AFH are often associated with a significant lymphocytic infiltrate, with germinal center formation, the lesions do not appear to arise in lymph nodes on close histological examination. The ability of these lesions to simulate involvement of a lymph node may lead to misinterpretation as nodal metastasis particularly in recurrent cases. It has been suggested that the spindle cells of this lesion may show the differentiation toward the lineage of fibroblastic reticulum cells [8] which are a component of the non-lymphoid, non-vascular stroma of lymph nodes based on histologic and immunophenotypic features. This could explain the peculiar association with lymphoid tissue, though the lineage of differentiation of this tumor is certainly not understood. From a diagnostic perspective, it is important to remember that lymphoid tissue and hemorrhage can be minimal to absent leaving only the characteristic spindle cells. Using cytogenetics, several cases were initially described with translocations between the EWSR1 (22q12) and ATF1 (12q13). [12, 13, 14] Further analysis revealed that the EWSR1-ATF1 fusion transcripts demonstrated were identical to those encountered in clear cell sarcoma (CCS), but these were present in only a small subset of investigated cases. FUS (16p11) was seen to substitute for EWSR1 in an additional case. [15] Antonescu and colleagues demonstrated that primary clear cell sarcoma of the gastrointestinal tract (GI-CCS) was often associated with fusion genes formed by EWSR1 and CREB1 (2q33), [16] a close homolog of ATF1 that is also activated by cyclic AMP (cAMP). Antonescu and colleagues subsequently demonstrated that EWSR1-CREB1 was the most common fusion event in AFH, [17] and was again identical to that seen in GI-CCS. Others have confirmed this finding [18] and evidence indicates that the EWSR1-CREB1 fusion is present in the majority of AFH cases with EWSR1-ATF1 and FUS-ATF1 seen in a smaller portion of cases. This can be exploited diagnostically using either FISH or reverse transcription PCR to confirm a suspected diagnosis of AFH. The EWSR1-ATF1 fusion protein appears to bind cAMP responsive elements (CREs) in the promoter region of genes and acts as an aberrant transcription factor no longer regulated by cAMP. [19] Interestingly, the consequences of the EWSR1-ATF1 fusion transcript are different depending on the tumor. For instance, in CCS, the EWSR1-ATF1 fusion transcript induces expression the melanocytic master regulatory gene, microopthalmia transcription factor (MITF), that ultimately promotes the production of melanosomes among its other functions. [17, 20, 21] In contrast, MITF expression is not seen in AFH associated with EWSR1-ATF1. [12, 17] The EWSR1-CREB1 does not appear to be associated with melanocytic differentiation in either GI-CCS or AFH. [16, 17] Perhaps when and where (precise cell type, state of differentiation and environment) the fusion gene is expressed leads to two different tumors, AFH and CCS, with very different histologic properties and natural histories. The recent work of Capecchi and colleagues to produce mouse models of alveolar rhabdomyosarcoma (RMS) [22, 23] and synovial sarcoma [24, 25] and by others in a Drosophila model of alveolar RMS [26] supports this idea that the fusion products produce tumors only when expressed in certain cell types at specific stages of development.

Bullet points :
It is not possible to given helpful bullet points in the absence of the diagnosis as these would be non-specific and general and helpful to this particular case.

References:
  1. Calonje E, Fletcher CD. Aneurysmal benign fibrous histiocytoma: clinicopathological analysis of 40 cases of a tumour frequently misdiagnosed as a vascular neoplasm. Histopathology. Apr 1995;26(4):323-331.

  2. Calonje E, Mentzel T, Fletcher CD. Cellular benign fibrous histiocytoma. Clinicopathologic analysis of 74 cases of a distinctive variant of cutaneous fibrous histiocytoma with frequent recurrence. Am J Surg Pathol. Jul 1994;18(7):668-676.

  3. Fletcher CD. Benign fibrous histiocytoma of subcutaneous and deep soft tissue: a clinicopathologic analysis of 21 cases. Am J Surg Pathol. Sep 1990;14(9):801-809.

  4. Perkins P, Weiss SW. Spindle cell hemangioendothelioma. An analysis of 78 cases with reassessment of its pathogenesis and biologic behavior. Am J Surg Pathol. Oct 1996;20(10):1196-1204.

  5. Hong A, Davies S, Lee CS. Immunohistochemical detection of the human herpes virus 8 (HHV8) latent nuclear antigen-1 in Kaposi's sarcoma. Pathology. Oct 2003;35(5):448-450.

  6. Lyons LL, North PE, Mac-Moune Lai F, Stoler MH, Folpe AL, Weiss SW. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol. May 2004;28(5):559-568.

  7. Enzinger FM. Angiomatoid malignant fibrous histiocytoma: a distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm. Cancer. Dec 1979;44(6):2147-2157.

  8. Fanburg-Smith JC, Miettinen M. Angiomatoid "malignant" fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype. Hum Pathol. Nov 1999;30(11):1336-1343.

  9. Costa MJ, Weiss SW. Angiomatoid malignant fibrous histiocytoma. A follow-up study of 108 cases with evaluation of possible histologic predictors of outcome. Am J Surg Pathol. Dec 1990;14(12):1126-1132.

  10. Fletcher CDM, Unni KK, Mertens F. World Health Organization Classification of Tumours: Pathology and Genetics, Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002.

  11. Smith ME, Costa MJ, Weiss SW. Evaluation of CD68 and other histiocytic antigens in angiomatoid malignant fibrous histiocytoma. Am J Surg Pathol. Aug 1991;15(8):757-763.

  12. 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 histiocytoma. Genes Chromosomes Cancer. Sep 2005;44(1):97-102.

  13. Hallor KH, Micci F, Meis-Kindblom JM, et al. Fusion genes in angiomatoid fibrous histiocytoma. Cancer Lett. Jun 18 2007;251(1):158-163.

  14. Raddaoui E, Donner LR, Panagopoulos I. Fusion of the FUS and ATF1 genes in a large, deep-seated angiomatoid fibrous histiocytoma. Diagn Mol Pathol. Sep 2002;11(3):157-162.

  15. 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 16p11. Cancer Genet Cytogenet. Sep 2000;121(2):109-116.

  16. Antonescu CR, Nafa K, Segal NH, Dal Cin P, Ladanyi M. EWS-CREB1: a recurrent variant fusion in clear cell sarcoma--association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res. Sep 15 2006;12(18):5356-5362.

  17. Antonescu CR, Dal Cin P, Nafa K, et al. EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer. Dec 2007;46(12):1051-1060.

  18. Rossi S, Szuhai K, Ijszenga M, et al. EWSR1-CREB1 and EWSR1-ATF1 Fusion Genes in Angiomatoid Fibrous Histiocytoma. Clin Cancer Res. Dec 15 2007;13(24):7322-7328.

  19. Fujimura Y, Siddique H, Lee L, Rao VN, Reddy ES. EWS-ATF-1 chimeric protein in soft tissue clear cell sarcoma associates with CREB-binding protein and interferes with p53-mediated trans-activation function. Oncogene. Oct 11 2001;20(46):6653-6659.

  20. Davis IJ, Kim JJ, Ozsolak F, et al. Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers. Cancer Cell. Jun 2006;9(6):473-484.

  21. Antonescu CR, Tschernyavsky SJ, Woodruff JM, Jungbluth AA, Brennan MF, Ladanyi M. Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases. J Mol Diagn. Feb 2002;4(1):44-52.

  22. Keller C, Arenkiel BR, Coffin CM, El-Bardeesy N, DePinho RA, Capecchi MR. Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev. Nov 1 2004;18(21):2614-2626.

  23. Keller C, Capecchi MR. New genetic tactics to model alveolar rhabdomyosarcoma in the mouse. Cancer Res. Sep 1 2005;65(17):7530-7532.

  24. Davis SR, Meltzer PS. Modeling synovial sarcoma: timing is everything. Cancer Cell. Apr 2007;11(4):305-307.

  25. Haldar M, Hancock JD, Coffin CM, Lessnick SL, Capecchi MR. A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell. Apr 2007;11(4):375-388.

  26. Galindo RL, Allport JA, Olson EN. A Drosophila model of the rhabdomyosarcoma initiator PAX7-FKHR. Proc Natl Acad Sci U S A. Sep 5 2006;103(36):13439-13444.