Based on the history, physical examination, laboratory studies, imaging studies, and histologic picture, what is the diagnosis and how should this lesion be treated?
The tumor was comprised of plump atypical spindle and ovoid cells arranged in a fascicular or herringbone-type pattern (Fig. 5). The cells appeared immature with minimal to mild eosinophilic fibrillary cytoplasm. There was minimal pleomorphism and frequent mitoses (10-11 per 5 high power fields.) The mass also contained scattered amounts of chronic mononuclear inflammatory cells (Fig. 6). Focal areas of hemorrhage and necrosis also were identified. Immunohistochemical staining for CD34, CD31, Factor VIII, HHF-35, SMA, desmin, S-100, and keratin were all negative. CD99 was positive. Ki-67 (proliferative index) was approximately 20% to 30%. FISH analysis for FKHR on 13q14, SYT on 18q11.2, and EWSR on 22q12 were negative. Reverse-transcription polymerase chain reaction (RT-PCR) was positive for ETV6/NTRK3 t(12;15)(q13;q25) translocation.
The differential diagnosis for a soft tissue mass in the extremity of an infant is broad, and includes benign and malignant processes, and congenital anomalies.
Hemangiomas are the most common tumor of infancy, occurring in 4% to 10% of infants [2, 15, 40], and approximately 15% of these lesions involve the extremities. Congenital hemangiomas differ as they are fully grown by birth and do not have the characteristic postnatal rapid growth phase, tending to involute after 1 year . Histologically, hemangiomas contain plump epithelial cells and lobules of benign-appearing capillaries, and have markers for vascular tumors [2, 15]. Vascular malformations can have similar clinical presentation at birth, but do not have the rapid growth pattern. MRI shows vascular channels and structures; lesions contain abnormal arterial, venous and lymphatic elements. Histologically these malformations are characterized by normal, mature vascular endothelium [26, 29].
Congenital or infantile fibrosarcoma is a rare fibroblastic tumor, but is the most common soft tissue sarcoma in patients younger than 1 year, with 1/3 of cases present at birth [8, 9, 18, 36]. Extremities are the most common location, whereas truncal lesions carry a poorer prognosis [4, 32]. Although histologically identical to the adult-type fibrosarcoma, there are distinct cytogenetic and clinical characteristics . Moreover, unlike its adult counterpart, congenital fibrosarcoma metastasizes in less than 10% of patients and carries a good prognosis, despite its ominous histologic appearance and locally aggressive behavior [3, 4, 14, 36]. Five- and 10-year survival rates are approximately 80% to 90% [6, 27, 30, 32], and amputation rates appear to be declining [3, 8, 30]
MRI findings are generally nonspecific, and show a well-circumscribed, heterogeneous mass, with vascular elements, areas of necrosis, and hemorrhage. The mass is typically isointense to muscle on T1-weighted images and heterogeneously hyperintense on T2-weighted images; gadolinium enhancement is variable [5, 24]. Although the lung is the most common site of metastases, congenital fibrosarcoma can metastasize to bone [3, 36], with technetium-99 bone scan being useful for detection of these metastases.
Microscopically, congenital fibrosarcoma is a hypercellular, hyperchromatic, anaplastic spindle cells tumor arranged in a herringbone pattern, with frequent mitoses, necrosis, and hemorrhage . Immunohistochemistry and cytogenetics often are needed, and show negative staining for SMA, S-100, desmin, CD31, and CD34 . Congenital fibrosarcoma is characterized by a recurrent t(12;15)(p13;q25) rearrangement, producing the ETV6 (TEL):NTRK3 (neurotrophin-3 receptor) fusion protein identified by RT-PCR [20, 34] and not expressed by the adult-type fibrosarcoma .
The treatment for congenital fibrosarcoma is multimodal, but the mainstay is surgical excision. Although the adoption of limb-salvage techniques has been proposed, the overall amputation rate for congenital fibrosarcoma still approaches 50% [3, 8, 30], and it is not always clear which patients will have postsurgical local recurrence. Chemoresponsiveness of congenital fibrosarcoma is unclear [6, 30], however neoadjuvant chemotherapy may be used, in an attempt to decrease tumor size and reduce the surgical morbidity. Chemotherapy also has been used for unresectable lesions [3, 16, 17, 22, 27, 37]. The most common regimen used combines vincristine, actinomycin D, and cyclophosphamide (VAC) [6, 30]; its side effect is well established and is tolerable in infants [10, 22, 23].
In our patient, neoadjuvant chemotherapy with three courses of VAC and one course exchanging actinomycin D for Adriamycin® (Pharmacia, Kalamazoo, MI) was used in an attempt to reduce the size of the tumor. Except for intratumoral bleeding, there was no significant change. Limb-salvage surgery was performed with microdissection of the brachial plexus and wide excision of the mass with free margins. Postoperative chemotherapy was not administered, owing to the poor response (< 80% necrosis) and negative margins. At 2 years followup, the patient is continuously free of disease, and has recovered full ROM of her shoulder and elbow with no functional deficit.
We present the case of a patient with congenital fibrosarcoma treated with a limb-salvage strategy using neoadjuvant chemotherapy and wide surgical excision. It is still unclear whether there are specific attributes of congenital fibrosarcoma that confer chemoresponsiveness; our patient had some tumor necrosis without a reduction in tumor size. Nonetheless, given some successes reported in the literature, it is not unreasonable to include neoadjuvant chemotherapy in the overall treatment armamentarium when considering limb-salvage strategies. As we progress toward better comprehension of tumor characterization, behavior and treatment response patterns, we move away from highly morbid amputations as the mainstay of treatment for congenital fibrosarcoma.
We thank Dr. Milan Stevanovic for microsurgery expertise and Dr. William A. May for contributions to the discussion and management regarding chemotherapy for this patient.
1. Alaggio, R., Barisani, D., Ninfo, V., Rosolen, A. and Coffin, CM. Morphologic overlap between infantile myofibromatosis and infantile fibrosarcoma: a pitfall in diagnosis. Pediatr Dev Pathol.
2008; 11: 355-362. 10.2350/07-09-0355.1
2. Berenguer, B., Mulliken, JB., Enjolras, O., Boon, LM., Wassef, M., Josset, P., Burrows, PE., Perez-Atayde, AR. and Kozakewich, HP. Rapidly involuting congenital hemangioma: clinical and histopathologic features. Pediatr Dev Pathol.
2003; 6: 495-510. 10.1007/s10024-003-2134-6
3. Blocker, S., Koenig, J. and Ternberg, J. Congenital fibrosarcoma. J Pediatr Surg.
1987; 22: 665-670. 10.1016/S0022-3468(87)80123-9
4. Bourgeois, JM., Knezevich, SR., Mathers, JA. and Sorensen, PHB. Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors. Am J Surg Pathol.
2000; 24: 937-946. 10.1097/00000478-200007000-00005
5. Canale, S., Vanel, D., Couanet, D., Patte, C., Caramella, C. and Dromain, C. Infantile fibrosarcoma: magnetic resonance imaging findings in six cases. Eur J Radiol.
2009; 72: 30-37. 10.1016/j.ejrad.2009.05.036
6. Cecchetto, G., Carli, M., Alaggio, R., Dall’Igna, P., Bisogno, G., Scarzello, G., Zanetti, I., Durante, G., Inserra, A., Siracusa, F., Guglielmi, M. Italian Cooperative Group Fibrosarcoma in pediatric patients: results of the Italian Cooperative Group studies (1979-1995). J Surg Oncol
2001; 78: 225-231. 10.1002/jso.1157
7. Chung, EB. and Enzinger, FM. Infantile myofibromatosis. Cancer.
1981; 48: 1807-1818. 10.1002/1097-0142(19811015)48:8<1807::AID-CNCR2820480818>3.0.CO;2-G
8. Coffin, CM. and Dehner, LP. Soft tissue tumors in the first year of life: a report of 190 cases. Pediatr Pathol.
1990; 10: 509-526. 10.3109/15513819009067140
9. Coffin, CM., Jaszcz, W., O’Shea, PA. and Dehner, LP. So-called congenital-infantile fibrosarcoma: does it exist and what is it? Pediatr Pathol.
1994; 14: 133-150. 10.3109/15513819409022033
10. Crist, WM., Anderson, JR., Meza, JL., Fryer, C., Raney, RB., Ruymann, FB., Breneman, J., Qualman, SJ., Wiener, E., Wharam, M., Lobe, T., Webber, B., Maurer, HM. and Donaldson, SS. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol.
2001; 19: 3091-3102.
11. Enzinger, FM. and Weiss, SW. In: Weiss, SW. and Goldblum, JR. (eds.), Fibrosarcoma. Enzinger and Weiss’s Soft Tissue Tumors.
2001. 4th ed. St Louis, MO: Mosby Inc. 409-441.
12. Ernemann, U., Kramer, U., Miller, S., Bisdas, S., Rebmann, H., Brueuninger, H., Zwick, C. and Hoffmann, J. Current concepts in the classification: diagnosis and treatment of vascular anomilies. Eur J Radiol.
2010; 75: 2-11. 10.1016/j.ejrad.2010.04.009
13. Ferrari, A., Casanova, M., Bisogno, G., Zanetti, I., Cecchetto, G., DeBernardi, B., Riccardi, R., Tamaro, P., Meazza, C., Alaggio, R., Ninfo, V., Carli, M. Italian Cooperative Group Rhabdomyosarcoma in infants younger than one year old: a report from the Italian Cooperative Group. Cancer.
2003; 97: 2597-2604. 10.1002/cncr.11357
14. Fisher, C. Fibromatosis and fibrosarcoma in infancy and childhood. Eur J Cancer.
1996; 32A: 2094-2100. 10.1016/S0959-8049(96)00287-0
15. Goh, SG. and Calonje, E. Cutaneous vascular tumours: an update. Histopathology.
2008; 52: 661-673. 10.1111/j.1365-2559.2007.02924.x
16. Grier, HE., Perez-Atayde, AR. and Weinstein, HJ. Chemotherapy for inoperable infantile fibrosarcoma. Cancer.
1985; 56: 1507-1510. 10.1002/1097-0142(19851001)56:7<1507::AID-CNCR2820560705>3.0.CO;2-7
17. Grohn, ML., Borzi, P., Mackay, A. and Suppiah, R. Management of extensive congenital fibrosarcoma with preoperative chemotherapy. ANZ J Surg.
2004; 74: 919-921. 10.1111/j.1445-1433.2004.03181.x
18. Gurney JG, Smith MA, Ross JA. Cancer Among Infants. In: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995.
National Cancer Institute, Cancer Statistics Branch, SEER Program. Bethesda, MD: National Cancer Institute; 1999; NIH Pub. No. 99-4649.
19. Heim-Hall, J. and Yohe, SL. Application of immunohistochemistry to soft tissue neoplasms. Arch Pathol Lab Med.
2008; 132: 476-489.
20. Knezevich, SR., McFadden, DE., Tao, W., Lim, JF. and Sorensen, PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nature Genet.
1998; 18: 184-187. 10.1038/ng0298-184
21. Koujok, K., Ruiz, RE. and Hernandez, RJ. Myofibromatosis: imaging characteristics. Pediatr Radiol.
2005; 35: 374-380. 10.1007/s00247-004-1357-7
22. Kurkchubasche, AG., Halvorson, EG., Forman, EN., Terek, RM. and Ferguson, WS. The role of preoperative chemotherapy in the treatment of infantile fibrosarcoma. J Pediatr Surg.
2000; 35: 880-883. 10.1053/jpsu.2000.6871
23. Kynaston, JA., Malcom, AJ., Craft, AW., Davies, SM., Jones, PH., King, DJ., Mitchell, CD., Oakhill, A. and Stiller, CA. Chemotherapy in the management of infantile fibrosarcoma. Med Pediatr Oncol.
1993; 21: 488-493. 10.1002/mpo.2950210706
24. Laffan, EE., Ngan, BY. and Navarro, OM. Pediatric soft-tissue tumors and pseudotumors: MR imaging features with pathologic correlation: Part 2: Tumors of fibroblastic/myofibroblastic, so-called fibrohistiocytic, muscular, lymphomatous, neurogenic, hair matrix and uncertain origin. Radiographics.
2009; 29: e36. 10.1148/rg.e36
25. Laor, T.MR imaging of soft tissue tumors and tumor-like lesions. Pediatr Radiol.
2004; 34: 24-37. 10.1007/s00247-003-1086-3
26. Lee, BB. Critical issues in management of congenital vascular malformation. Ann Vasc Surg.
2004; 18: 380-392. 10.1007/s10016-004-0020-y
27. Loh, ML., Ahn, P., Perez-Atayde, AR., Gebhardt, MC., Shamberger, RC. and Grier, HE. Treatment of infantile fibrosarcoma with chemotherapy and surgery: results from the Dana-Farber Cancer Institute and Children’s Hospital, Boston. J Pediatr Hematol Oncol.
2002; 24: 722-726. 10.1097/00043426-200212000-00008
28. Mentzel, T., Calonje, E., Nascimento, AG. and Fletcher, CDM. Infantile hemangiopericytoma versus infantile myofibromatosis: study of a series suggesting a continuous spectrum of infantile myofibroblastic lesions. Am J Surg Pathol.
1994; 18: 922-930. 10.1097/00000478-199409000-00007
29. Mulliken, JB. and Glowacki, J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg.
1982; 69: 412-422. 10.1097/00006534-198203000-00002
30. Orbach, D., Rey, A., Cecchetto, C., Oberlin, O., Casanova, M., Thebaud, E., Scopinaro, M., Bisogno, G., Carli, M. and Ferrari, A. Infantile fibrosarcoma: management based on the European experience. J Clin Oncol.
2010; 28: 318-323. 10.1200/JCO.2009.21.9972
31. Pastore, G., Peris-Bonet, R., Carli, M., Martínez-García, C., Sánchez de Toledo, J. and Steliarova-Foucher, E. Childhood soft tissue sarcomas incidence and survival in European children (1978-1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer.
2006; 42: 2136-2149. 10.1016/j.ejca.2006.05.016
32. Pritchard, DJ., Soule, EH., Taylor, WF. and Ivins, JC. Fibrosarcoma: a clinicopathologic and statistical study of 199 tumors of the soft tissues of the extremities and trunk. Cancer.
1974; 33: 888-897. 10.1002/1097-0142(197403)33:3<888::AID-CNCR2820330339>3.0.CO;2-C
33. Sandberg, AA. and Bridge, JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: congenital (infantile) fibrosarcoma and mesoblastic nephroma. Cancer Genet Cytogenet.
2002; 132: 1-13. 10.1016/S0165-4608(01)00528-3
34. Sheng, WQ., Hisaoka, M., Okamoto, S., Tanaka, A., Meis-Kindblom, JM., Kindblom, LG., Ishida, T., Nojima, T. and Hashimoto, H. Congenital-infantile fibrosarcoma: a clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues. Am J Clin Pathol.
2001; 115: 348-355. 10.1309/3H24-E7T7-V37G-AKKQ
35. Soper, JR. and Silva, M. Infantile myofibromatosis: a radiologic review. Pediatr Radiol.
1993; 23: 189-194. 10.1007/BF02013829
36. Soule, EH. and Pritchard, DJ. Fibrosarcoma in infants and children: a review of 110 cases. Cancer.
1977; 40: 1711-1721. 10.1002/1097-0142(197710)40:4<1711::AID-CNCR2820400447>3.0.CO;2-9
37. Surico, G., Muggeo, P., Daniele, RM., Novielli, C., Rigillo, N. and Minervini, C. Letters to the Editor. Chemotherapy alone for the treatment of congenital fibrosarcoma: is surgery always needed? Med Pediatr Oncol
2003; 40: 268-270. 10.1002/mpo.10150
38. Wexler, LH. and Helman, LJ. Pediatric soft tissue sarcomas. CA Cancer J Clin.
1994; 44: 211-247. 10.3322/canjclin.44.4.211
39. Wiswell, TE., Davis, J., Cunningham, BE., Solenberger, R. and Thomas, PJ. Infantile myofibromatosis: the most common fibrous tumor of infancy. J Pediatr Surg.
1988; 23: 315-318. 10.1016/S0022-3468(88)80196-9
40. Yan, AC., Chamlin, SL., Liang, MG., Hoffman, B., Attiyeh, EF., Chang, B. and Honig, PJ. Congenital infantile fibrosarcoma: a masquerader of ulcerated hemangioma. Pediatr Dermatol.
2006; 23: 330-334. 10.1111/j.1525-1470.2006.00257.x