CLINICAL ARTICLE
Congenital-Infantile Fibrosarcoma Presenting as a Hemangioma A Case Report Melissa Kanack, BA,* Jessica Collins, MD,†‡ Timothy J. Fairbanks, MD,§|| and Amanda Gosman, MD*§ Introduction: Congenital-infantile fibrosarcoma (CIFS) is a rare pediatric soft tissue tumor that on initial clinical presentation can mimic an infantile hemangioma. Management of these conditions differs drastically, and delay in diagnosis and treatment may affect prognosis. Methods: A 6-month-old male infant originally presented to dermatology for evaluation of a suspected right buttock hemangioma, present at birth as a small red mass just lateral to the gluteal cleft. The lesion rapidly grew over 2 weeks to a size of 4 4.5 4.5 cm, with violaceous color change and central ulceration. The patient received a course of cephalexin; however, the mass became painful with several episodes of bleeding and did not show clinical improvement. Magnetic resonance imaging and ultrasound supported the diagnosis of atypical hemangioma. Results: Plastic Surgery was consulted for excision due to recurrent bleeding. An excisional biopsy was undertaken and pathologic finding showed CIFS. The case was discussed with Hematology/Oncology and Pediatric Surgery, and the patient underwent re-excision and obtained clear margins. Initial metastatic workup was negative; however, patient had evidence of recurrent disease as well as pulmonary metastasis on his most recent surveillance imaging. He underwent re-excision of the gluteal mass and is currently receiving adjuvant chemotherapy. Conclusions: This case demonstrates a rare malignancy initially misdiagnosed as a hemangioma. Consideration of CIFS is crucial in cases of complicated hemangiomas not responding to standard treatment. Treatment calls for excision with wide margins and/or adjuvant chemotherapy if excision is not possible. Classic pathologic findings, immunohistochemistry, and/or reverse transcription-polymerase chain reaction can confirm the diagnosis. A correct and rapid diagnosis of CIFS is critical to optimizing treatment and subsequent prognosis. Key Words: congenital-infantile fibrosarcoma, vascular tumors, hemangioma, infantile hemangioma, sarcoma (Ann Plast Surg 2015;74: S25–S29)
C
ongenital-infantile fibrosarcoma (CIFS) is a rare tumor representing less than 1% of all childhood cancers but constituting 5% to 10% of sarcoma diagnoses in children.1 Many patients present in the first year of life, and virtually all by 5 years.2 Infantile hemangiomas are common, occurring in up to 10% of all infants and often rapidly proliferate, stabilize, and involute without additional treatment.3 The highly vascularized appearance of CIFS and the potential for ulceration in rapidly proliferating infantile hemangiomas can lead to an initial misdiagnosis and subsequent delay in treatment of CIFS, with potential impact on prognosis Received July 7, 2014, and accepted for publication, after revision, September 25, 2014. From the *Division of Plastic Surgery, Department of Surgery, University of California San Diego; †Oasis MD; ‡Department of Surgery, University of California San Diego; §Rady Children's Hospital-San Diego; and ||Division of Pediatric Surgery, Department of Surgery, University of California San Diego, San Diego, CA. Conflicts of interest and sources of funding: none declared. Reprints: Amanda Gosman, MD, Division of Plastic Surgery, Department of Surgery, University of California, San Diego, 200 W Arbor Dr, San Diego, CA 92103-8890. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0148-7043/15/7401–S025 DOI: 10.1097/SAP.0000000000000376
Annals of Plastic Surgery • Volume 74, Supplement 1, May 2015
and outcomes. Congenital-infantile fibrosarcoma can be differentiated from infantile hemangioma using histopathologic, immunohistochemical, and reverse transcription-polymerase chain reaction (RT-PCR) techniques4,5; however, the clinician must first have an index of suspicion for considering this diagnosis in assessing the child with a mass resembling a hemangioma, especially with rapid growth, ulceration, fixation, resistance to standard therapy, or other atypical features. A case is described in which a 6-month-old male infant presented for excision of a presumed ulcerated hemangioma with recurrent episodes of bleeding as the main indication for the procedure, but was ultimately diagnosed on pathologic finding with CIFS.
CASE REPORT The patient was a 6-month-old male infant who had been followed by Dermatology for a small red mass on his right buttock present at birth and suspected to be a hemangioma. The mass had been noted to be slowly enlarging until 2 weeks before presentation, when it rapidly enlarged to a size of 4 4.5 4.5 cm with violaceous changes and central ulceration (Fig. 1). The patient presented to dermatology clinic and was treated with cephalexin for an initial diagnosis of ulcerated infantile hemangioma with possible superinfection. At follow-up in 1 week, there was no improvement, the lesion had become painful, and the patient had several episodes of bleeding, so he was admitted for further imaging and treatment. Initial workup performed included magnetic resonance imaging (MRI), ultrasound, cultures, and blood work. Magnetic resonance imaging (Fig. 2) was suggestive of a subcutaneous mass with skin involvement, with differential diagnosis including atypical hemangioma, CIFS, or rhabdomyofibroma. Ultrasound was used to assess vascular flow and also supported the diagnosis of atypical hemangioma. Wound cultures grew Staphylococcus aureus, fungal, anaerobic, and acid-fast bacilli cultures were negative, and complete blood cell count was within normal limits. On the basis of clinical picture, the lesion was considered to be a hemangioma and plastic surgery was consulted for excision due to recurrent bleeding and ulceration. An excisional biopsy was performed demonstrating an exophytic lesion with extension down to subcutaneous fat but without violation of the muscular fascia. The lesion was excised as a single unit with a rim of normal tissue surrounding and sent for pathologic examination. Pathologic finding returned with a diagnosis of CIFS (Fig. 3). On histopathology, CIFS is classically described as a solid dense proliferation of spindle cells forming a herringbone pattern.5 On immunohistochemistry, the cells were positive for vimentin and CD34 and negative for S100, smooth muscle actin, desmin, and myogenin, consistent with diagnosis of a fibrosarcoma.6 Reverse transcription-polymerase chain reaction has also been used to aid in the diagnosis of CIFS by assessing for the ETV6-NTRK3 fusion transcript resulting from the t(12;15)(p12; q25) chromosomal translocation5; in this case, the tissue sample RT-PCR was negative. However, pathologic finding, imaging, and clinical presentation were consistent with and strongly suggestive of CIFS and this diagnosis was maintained. Other findings on pathology included dilated blood vessels, invasion of associated fat, and positive peripheral margins. www.annalsplasticsurgery.com
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MRI was obtained 6 weeks postoperatively and then surveillance was recommended with chest CT, abdominal/pelvic/sacral MRI, and bone scan every 3 months for 1 year. The patient had an uneventful postoperative course and recovery. Sacral MRI performed at 1 month had no evidence of recurrence, and his subsequent 4-month postoperative scans were also without evidence of recurrent or metastatic disease. However, on his next set of surveillance imaging at 9 months, he was noted to have a new 1-cm right gluteal mass as well as new pulmonary nodules concerning for lung metastasis. At this time, Hematology/Oncology met with the family and recommended surgical resection of the recurrent tumor in the gluteal region as well as adjuvant chemotherapy. He was taken to the operating room with Pediatric Surgery for re-excision of the right gluteal mass. Pathologic finding was similar to the original tumor, demonstrating spindle cells in a herringbone pattern infiltrating skeletal muscle with no vascular invasion seen; clear surgical margins were attained. One month after this resection, he began chemotherapy with vincristine, actinomycin-D, and cyclophosphamide with plan for 4 cycles and subsequent re-imaging and disease assessment.
DISCUSSION
FIGURE 1. Lesion as it appeared at presentation, measuring 4.5 4.5 4 cm, after initial excision, and at 9 months postoperative follow-up. The patient was well healed from his repeat excision, although imaging at this time demonstrated evidence of recurrent and metastatic disease.
The case was reviewed at tumor board in collaboration with the Pediatric Surgery and Hematology/Oncology teams. Literature suggests that patients with CIFS may be observed without need for further chemotherapy if negative margins are achieved7; therefore, Hematology/ Oncology recommended repeat excision with at least 5-mm margins. The patient also underwent a metastatic workup including a bone scan and computed tomographic (CT) scan of the chest, with no evidence of skeletal or pulmonary metastasis. Therefore, re-excision was performed with intraoperative frozen sections demonstrating attainment of 1-cm clear margins. Per the recommendations of Hematology/Oncology, the patient was not treated with adjuvant chemotherapy; a repeat sacral S26
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This case is unique in comparison to many of the other reported cases of CIFS initially diagnosed as a benign vascular malformation and merits discussion on several points, including the location of the tumor, histopathologic characteristics, and metastatic behavior. Several of the reported cases of CIFS initially diagnosed as hemangiomas involve lesions located on the extremities and describe a large tumor present at birth associated with significant bleeding and coagulopathy necessitating immediate intervention.1,8–11 In comparison, CIFS located on the head, neck, trunk, and pelvis are uncommon, accounting for only 30% of all reported cases, although primary lesions have been reported in even more unusual locations including the lungs and retroperitoneum.1,9,12 Therefore, although the patient's mass was present at birth, it was small and located on the pelvis, both unusual for CIFS. In other cases that did not require intervention at birth, a similar picture is described in which a small lesion present at birth was diagnosed as a infantile hemangioma and managed conservatively in anticipation of involution, but then exhibited rapid growth and ulceration.4,13 Of note, infantile hemangiomas are usually not present at birth, but appear within the first few weeks of life and are then characterized by a few months of rapid growth followed by involution over several years; during this period they are managed conservatively with observation, medically with propranolol, corticosteroids, or other therapeutics, or with laser therapy as indicated.3 Congenital hemangiomas, of which rapidly involuting and noninvoluting types have been described, are another rare vascular malformation that in contrast to infantile hemangiomas present fully developed at birth.14 These lesions are often large and may ulcerate, and studies have reported nonspecific findings in attempting to differentiate congenital hemangiomas from CIFS and arteriovenous malformations using angiography.15 However, although a noninvoluting congenital hemangioma may grow with the child, congenital hemangiomas do not demonstrate the sudden rapid growth often described in CIFS or infantile hemangiomas.14 Therefore, a vascular appearing lesion truly “present since birth” and presenting with a rapid increase in size or other concerning features should merit consideration of CIFS and biopsy. In addition, ulceration, fixation to surrounding tissues, and recurrent bleeding episodes in combination with an increase in size of a presumed congenital hemangioma as described by Yan and colleagues4 should merit reconsideration of this diagnosis and possible biopsy. Although this patient had no laboratory abnormalities upon presentation, it should be noted that coagulopathies have been described for both hemangiomas and CIFS. Kasabach-Merritt syndrome involving thrombocytopenic purpura may be seen in association with hemangiomas and other vascular malformations, whereas consumptive © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Annals of Plastic Surgery • Volume 74, Supplement 1, May 2015
CIFS Presenting as Hemangioma
FIGURE 2. Preoperative MRI imaging. A and B, Axial views. C and D, Sagittal views. B and C, T1-weighted images; A and D, T2-weighted images.
coagulopathy and disseminated intravascular coagulation may be a sign of malignancy and CIFS, and the 2 may be difficult to distinguish.8 Several case reports describe a large vascular lesion present at birth with coagulopathy initially thought to be Kasabach-Merritt associated with hemangioma, but in actuality, with manifestation of consumptive coagulopathy in conjunction with diagnosis of CIFS, diagnosed as disseminated intravascular coagulation associated with malignancy.9–11,13 Several of these authors also report a delay in diagnosis resulting in treatment of the lesion with corticosteroids as would be appropriate therapy for hemangioma with associated Kasabach-Merritt phenomenon, with diagnosis on biopsy after failure of the lesion to respond. On physical examination, some authors have noted subtle differences that may be useful in differentiating hemangiomas and CIFS; hemangiomas are reported as compressible and soft, whereas the tumor in CIFS is more firm and shiny in appearance.11,13 However, biopsy remains essential in diagnosis of CIFS and differentiation from atypical hemangioma or other vascular malformation, with immunohistochemistry for fibrosarcoma markers (vimentin positive, S100 negative) and RT-PCR for the ETV6-NTRK3 gene product to further aid in confirming the diagnosis. Although the histologic appearance of the tumor in this case was consistent with CIFS, it was atypical in that RT-PCR for ETV6-NTRK3 was negative, and the tumor was positive for CD34 in addition to vimentin on immunohistochemistry. Although vimentin is essentially positive in all fibrosarcomas, CD34 is less common but still consistent with this diagnosis.16 The t(12;15)(p12;q25) translocation has been noted to be present in most, but not all cases of © 2015 Wolters Kluwer Health, Inc. All rights reserved.
CIFS, and the ETV6-NTRK3 product has been noted as a key marker for differentiation of CIFS from other spindle cell tumors of childhood.5,16,17 Because of these unusual findings, the patient's tumor was sent for a second opinion, at which time dermatofibrosarcoma protuberans was suggested; however, the tumor was also negative for the platelet-derived growth factor receptor-beta rearrangement associated with this diagnosis. McCahon and colleagues18 have suggested that the presence of the ETV6-NTRK3 gene product may contribute to the chemosensitivity of these tumors; although this patient's response to chemotherapy remains to be determined, his unusual pathologic characteristics illustrate the difficulty in attaining a definitive diagnosis that may be used to guide therapeutics and assess treatment efficacy. Although imaging is useful in assessing the extent of the lesion, as this case demonstrates and several reports in the literature have confirmed, imaging findings in the case of CIFS and most of soft tissue tumors are nonspecific. Magnetic resonance imaging findings in CIFS typically include a well-circumscribed mass that is isointense to muscle on T1-weighted imaging and hyperintense on T2-weighted sequences, and larger tumors may demonstrate associated hemorrhage.19,20 When CIFS is confirmed, MRI is most useful for assessing soft tissue, vascular, and neural invasion to aid in treatment and surgical planning as well as for surveillance for disease recurrence after resection; CT is recommended if there is concern for bony involvement.6 Wide local excision remains the standard of care for treatment of CIFS, and children in whom negative margins are achieved may be observed without adjuvant radiation or chemotherapy.7 Therefore, www.annalsplasticsurgery.com
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primary surgical excision alone.25 Metastasis is rare, although with a higher rate of 26% reported in patients with axial primaries compared to 8% in those with extremity primaries.25 The lungs are the most frequent site of metastasis, with bone, brain, and adrenal glands as other reported metastatic sites.22 Although there are few reported data on the timing of metastasis, the patient in this report was at increased risk given the location of his primary tumor, and the rapid evolution of his recurrence and metastasis over 9 months after complete resection with negative margins emphasizes the importance of frequent surveillance in patients treated primarily with surgery.
CONCLUSIONS Congenital-infantile fibrosarcoma may mimic an atypical, ulcerated congenital or infantile hemangioma upon presentation, which has prognostic implications due to the potential for delay in diagnosis and thus initiation of appropriate treatment. In addition to initial presentation as an ulcerated hemangioma, this case also demonstrates a less common axial location of the tumor, atypical pathology, and metastatic and recurrent disease 9 months after initial resection. In particular, this serves to illustrate the complicated nature of these cases and emphasizes the high index of suspicion necessary in assessing an atypical lesion resembling a vascular malformation to make a rapid and correct diagnosis of CIFS. Further, this case demonstrates the important role of close surveillance in patients treated with excision as initial therapy for detection of disease recurrence and metastasis. REFERENCES
FIGURE 3. Pathologic specimen demonstrating dense proliferation of spindle cells in a herringbone pattern; the specimen also displayed a mitotic rate of up to 10 mitotic figures per high-power field.
lesions that could potentially be CIFS should be removed in a manner that will facilitate wide local excision with negative margins if needed. However, in the case of large lesions, especially those located on the distal extremities, use of neoadjuvant chemotherapy has been reported to decrease tumor bulk and thus reduce the need for amputation and enable a more conservative surgical approach.21 One case has been reported of a CIFS of the foot that resolved completely with chemotherapy, allowing the limb to be spared and emphasizing the chemosensitive nature of this tumor.22 Common chemotherapeutic regimens include vincristine, cyclophosphamide, and either adriamycin or actinomycin-D.23 Although radiation is not typically used in treatment of CIFS, it has been reported for emergent tracheal decompression in one case as well as in select cases with metastatic and recurrent disease.23 Compared to fibrosarcoma in adults as well as other aggressive spindle cell sarcomas of childhood, prognosis is generally viewed as good, with a 5-year survival rate of 84% in a case study of 85 patients.24 Local recurrence has been reported at a rate of 17% to 43% after S28
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1. Tarik E, Abdelouahed A, Tarik M, et al. Unusual case of congenital/infantile fibrosarcoma in a new born. Afr J Paediatr Surg. 2013;10:185. 2. Requena C, Miranda L, Cañete A, et al. Congenital fibrosarcoma simulating congenital hemangioma. Pediatr Dermatol. 2008;25:141–144. 3. Chen TS, Eichenfield LF, Friedlander SF. Infantile hemangiomas: an update on pathogenesis and therapy. Pediatrics. 2013;131:99–108. 4. Yan AC, Chamlin SL, Liang MG, et al. Congenital infantile fibrosarcoma: a masquerader of ulcerated hemangioma. Pediatr Dermatol. 2006;23:330–334. 5. Sheng WQ, Hisaoka M, Okamoto S, et al. Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6NTRK3 fusion transcripts using paraffin-embedded tissues. Am J Clin Pathol. 2001;115:348–355. 6. Braun P, Fernández-Montes JG, Calatayud AV. Congenital infantile fibrosarcoma: report of four cases and review of the literature. Eur J Radiol Extra. 2007;61: 33–39. 7. Cofer BR, Vescio PJ, Wiener ES. Infantile fibrosarcoma: complete excision is the appropriate treatment. Ann Surg Oncol. 1996;3:159–161. 8. Kerl K, Nowacki M, Leuschner I, et al. Infantile fibrosarcoma—an important differential diagnosis of congenital vascular tumors. Pediatr Hematol Oncol. 2012; 29:545–548. 9. Asgari M, Rubin BP, Hornung RL. Neonate with a fibrosarcoma and consumptive coagulopathy. J Am Acad Dermatol. 2004;50:23–25. 10. Muzaffar AR, Friedrich JB, Lu KK, et al. Infantile fibrosarcoma of the hand associated with coagulopathy. Plast Reconstr Surg. 2006;117:81e–86e. 11. Boon LM, Fishman SJ, Lund DP, et al. Congenital fibrosarcoma masquerading as congenital hemangioma: report of two cases. J Pediatr Surg. 1995;30: 1378–1381. 12. Akyuz C, Kupeli S, Varan A, et al. Infantile fibrosarcoma: retrospective analysis of eleven patients. Tumori. 2011;97:166–169. 13. Hayek SN, Janom HH, Ibrahim A, et al. Infantile fibrosarcoma misdiagnosed as vascular tumors. Hand. 2013;8:464–468. 14. Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting congenital hemangioma: clinical and histopathologic features. Pediatr Dev Pathol. 2003;6:495–510. 15. Konez O, Burrows PE, Mulliken JB, et al. Angiographic features of rapidly involuting congenital hemangioma (RICH). Pediatr Radiol. 2003;33:15–19. 16. Bourgeois JM, Knezevich SR, Mathers JA, et al. 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. 17. Guillou L, Folpe AL. Fibroblastic and fibrohistiocytic tumors. In: Folpe AL, Inwards CYeds. Bone and Soft Tissue Pathology. Philadelphia, PA; Churchill Livingston; 2010:43–96.
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18. McCahon E, Sorensen PH, Davis JH, et al. Non‐resectable congenital tumors with the ETV6–NTRK3 gene fusion are highly responsive to chemotherapy. Med Pediatr Oncol. 2003;40:288–292. 19. Canale S, Vanel D, Couanet D, et al. Infantile fibrosarcoma: magnetic resonance imaging findings in six cases. Eur J Radiol. 2009;72:30–37. 20. Ainsworth KE, Chavhan GB, Gupta AA, et al. Congenital infantile fibrosarcoma: review of imaging features. Pediatr Radiol. 2014;44:1124–1129. 21. Mnif H, Zrig M, Maazoun K, et al. Congenital infantile fibrosarcoma of the forearm. Chir Main. 2011;30:148–151.
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CIFS Presenting as Hemangioma
22. Demir HA, Akyüz C, Varan A, et al. Right foot congenital infantile fibrosarcoma treated only with chemotherapy. Pediatr Blood Cancer. 2010;54:618–620. 23. Loh ML, Ahn P, Perez-Atayde AR, et al. 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. 24. Chung E, Enzinger FM. Infantile fibrosarcoma. Cancer. 1976;38:729–739. 25. Shetty AK, Yu LC, Gardner RV, et al. Role of chemotherapy in the treatment of infantile fibrosarcoma. Med Pediatr Oncol. 1999;33:425–427.
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Congenital-Infantile Fibrosarcoma Presenting as a Hemangioma A Case Report Melissa Kanack, BA,* Jessica Collins, MD,†‡ Timothy J. Fairbanks, MD,§|| and Amanda Gosman, MD*§ Introduction: Congenital-infantile fibrosarcoma (CIFS) is a rare pediatric soft tissue tumor that on initial clinical presentation can mimic an infantile hemangioma. Management of these conditions differs drastically, and delay in diagnosis and treatment may affect prognosis. Methods: A 6-month-old male infant originally presented to dermatology for evaluation of a suspected right buttock hemangioma, present at birth as a small red mass just lateral to the gluteal cleft. The lesion rapidly grew over 2 weeks to a size of 4 4.5 4.5 cm, with violaceous color change and central ulceration. The patient received a course of cephalexin; however, the mass became painful with several episodes of bleeding and did not show clinical improvement. Magnetic resonance imaging and ultrasound supported the diagnosis of atypical hemangioma. Results: Plastic Surgery was consulted for excision due to recurrent bleeding. An excisional biopsy was undertaken and pathologic finding showed CIFS. The case was discussed with Hematology/Oncology and Pediatric Surgery, and the patient underwent re-excision and obtained clear margins. Initial metastatic workup was negative; however, patient had evidence of recurrent disease as well as pulmonary metastasis on his most recent surveillance imaging. He underwent re-excision of the gluteal mass and is currently receiving adjuvant chemotherapy. Conclusions: This case demonstrates a rare malignancy initially misdiagnosed as a hemangioma. Consideration of CIFS is crucial in cases of complicated hemangiomas not responding to standard treatment. Treatment calls for excision with wide margins and/or adjuvant chemotherapy if excision is not possible. Classic pathologic findings, immunohistochemistry, and/or reverse transcription-polymerase chain reaction can confirm the diagnosis. A correct and rapid diagnosis of CIFS is critical to optimizing treatment and subsequent prognosis. Key Words: congenital-infantile fibrosarcoma, vascular tumors, hemangioma, infantile hemangioma, sarcoma (Ann Plast Surg 2015;74: S25–S29)
C
ongenital-infantile fibrosarcoma (CIFS) is a rare tumor representing less than 1% of all childhood cancers but constituting 5% to 10% of sarcoma diagnoses in children.1 Many patients present in the first year of life, and virtually all by 5 years.2 Infantile hemangiomas are common, occurring in up to 10% of all infants and often rapidly proliferate, stabilize, and involute without additional treatment.3 The highly vascularized appearance of CIFS and the potential for ulceration in rapidly proliferating infantile hemangiomas can lead to an initial misdiagnosis and subsequent delay in treatment of CIFS, with potential impact on prognosis Received July 7, 2014, and accepted for publication, after revision, September 25, 2014. From the *Division of Plastic Surgery, Department of Surgery, University of California San Diego; †Oasis MD; ‡Department of Surgery, University of California San Diego; §Rady Children's Hospital-San Diego; and ||Division of Pediatric Surgery, Department of Surgery, University of California San Diego, San Diego, CA. Conflicts of interest and sources of funding: none declared. Reprints: Amanda Gosman, MD, Division of Plastic Surgery, Department of Surgery, University of California, San Diego, 200 W Arbor Dr, San Diego, CA 92103-8890. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0148-7043/15/7401–S025 DOI: 10.1097/SAP.0000000000000376
Annals of Plastic Surgery • Volume 74, Supplement 1, May 2015
and outcomes. Congenital-infantile fibrosarcoma can be differentiated from infantile hemangioma using histopathologic, immunohistochemical, and reverse transcription-polymerase chain reaction (RT-PCR) techniques4,5; however, the clinician must first have an index of suspicion for considering this diagnosis in assessing the child with a mass resembling a hemangioma, especially with rapid growth, ulceration, fixation, resistance to standard therapy, or other atypical features. A case is described in which a 6-month-old male infant presented for excision of a presumed ulcerated hemangioma with recurrent episodes of bleeding as the main indication for the procedure, but was ultimately diagnosed on pathologic finding with CIFS.
CASE REPORT The patient was a 6-month-old male infant who had been followed by Dermatology for a small red mass on his right buttock present at birth and suspected to be a hemangioma. The mass had been noted to be slowly enlarging until 2 weeks before presentation, when it rapidly enlarged to a size of 4 4.5 4.5 cm with violaceous changes and central ulceration (Fig. 1). The patient presented to dermatology clinic and was treated with cephalexin for an initial diagnosis of ulcerated infantile hemangioma with possible superinfection. At follow-up in 1 week, there was no improvement, the lesion had become painful, and the patient had several episodes of bleeding, so he was admitted for further imaging and treatment. Initial workup performed included magnetic resonance imaging (MRI), ultrasound, cultures, and blood work. Magnetic resonance imaging (Fig. 2) was suggestive of a subcutaneous mass with skin involvement, with differential diagnosis including atypical hemangioma, CIFS, or rhabdomyofibroma. Ultrasound was used to assess vascular flow and also supported the diagnosis of atypical hemangioma. Wound cultures grew Staphylococcus aureus, fungal, anaerobic, and acid-fast bacilli cultures were negative, and complete blood cell count was within normal limits. On the basis of clinical picture, the lesion was considered to be a hemangioma and plastic surgery was consulted for excision due to recurrent bleeding and ulceration. An excisional biopsy was performed demonstrating an exophytic lesion with extension down to subcutaneous fat but without violation of the muscular fascia. The lesion was excised as a single unit with a rim of normal tissue surrounding and sent for pathologic examination. Pathologic finding returned with a diagnosis of CIFS (Fig. 3). On histopathology, CIFS is classically described as a solid dense proliferation of spindle cells forming a herringbone pattern.5 On immunohistochemistry, the cells were positive for vimentin and CD34 and negative for S100, smooth muscle actin, desmin, and myogenin, consistent with diagnosis of a fibrosarcoma.6 Reverse transcription-polymerase chain reaction has also been used to aid in the diagnosis of CIFS by assessing for the ETV6-NTRK3 fusion transcript resulting from the t(12;15)(p12; q25) chromosomal translocation5; in this case, the tissue sample RT-PCR was negative. However, pathologic finding, imaging, and clinical presentation were consistent with and strongly suggestive of CIFS and this diagnosis was maintained. Other findings on pathology included dilated blood vessels, invasion of associated fat, and positive peripheral margins. www.annalsplasticsurgery.com
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MRI was obtained 6 weeks postoperatively and then surveillance was recommended with chest CT, abdominal/pelvic/sacral MRI, and bone scan every 3 months for 1 year. The patient had an uneventful postoperative course and recovery. Sacral MRI performed at 1 month had no evidence of recurrence, and his subsequent 4-month postoperative scans were also without evidence of recurrent or metastatic disease. However, on his next set of surveillance imaging at 9 months, he was noted to have a new 1-cm right gluteal mass as well as new pulmonary nodules concerning for lung metastasis. At this time, Hematology/Oncology met with the family and recommended surgical resection of the recurrent tumor in the gluteal region as well as adjuvant chemotherapy. He was taken to the operating room with Pediatric Surgery for re-excision of the right gluteal mass. Pathologic finding was similar to the original tumor, demonstrating spindle cells in a herringbone pattern infiltrating skeletal muscle with no vascular invasion seen; clear surgical margins were attained. One month after this resection, he began chemotherapy with vincristine, actinomycin-D, and cyclophosphamide with plan for 4 cycles and subsequent re-imaging and disease assessment.
DISCUSSION
FIGURE 1. Lesion as it appeared at presentation, measuring 4.5 4.5 4 cm, after initial excision, and at 9 months postoperative follow-up. The patient was well healed from his repeat excision, although imaging at this time demonstrated evidence of recurrent and metastatic disease.
The case was reviewed at tumor board in collaboration with the Pediatric Surgery and Hematology/Oncology teams. Literature suggests that patients with CIFS may be observed without need for further chemotherapy if negative margins are achieved7; therefore, Hematology/ Oncology recommended repeat excision with at least 5-mm margins. The patient also underwent a metastatic workup including a bone scan and computed tomographic (CT) scan of the chest, with no evidence of skeletal or pulmonary metastasis. Therefore, re-excision was performed with intraoperative frozen sections demonstrating attainment of 1-cm clear margins. Per the recommendations of Hematology/Oncology, the patient was not treated with adjuvant chemotherapy; a repeat sacral S26
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This case is unique in comparison to many of the other reported cases of CIFS initially diagnosed as a benign vascular malformation and merits discussion on several points, including the location of the tumor, histopathologic characteristics, and metastatic behavior. Several of the reported cases of CIFS initially diagnosed as hemangiomas involve lesions located on the extremities and describe a large tumor present at birth associated with significant bleeding and coagulopathy necessitating immediate intervention.1,8–11 In comparison, CIFS located on the head, neck, trunk, and pelvis are uncommon, accounting for only 30% of all reported cases, although primary lesions have been reported in even more unusual locations including the lungs and retroperitoneum.1,9,12 Therefore, although the patient's mass was present at birth, it was small and located on the pelvis, both unusual for CIFS. In other cases that did not require intervention at birth, a similar picture is described in which a small lesion present at birth was diagnosed as a infantile hemangioma and managed conservatively in anticipation of involution, but then exhibited rapid growth and ulceration.4,13 Of note, infantile hemangiomas are usually not present at birth, but appear within the first few weeks of life and are then characterized by a few months of rapid growth followed by involution over several years; during this period they are managed conservatively with observation, medically with propranolol, corticosteroids, or other therapeutics, or with laser therapy as indicated.3 Congenital hemangiomas, of which rapidly involuting and noninvoluting types have been described, are another rare vascular malformation that in contrast to infantile hemangiomas present fully developed at birth.14 These lesions are often large and may ulcerate, and studies have reported nonspecific findings in attempting to differentiate congenital hemangiomas from CIFS and arteriovenous malformations using angiography.15 However, although a noninvoluting congenital hemangioma may grow with the child, congenital hemangiomas do not demonstrate the sudden rapid growth often described in CIFS or infantile hemangiomas.14 Therefore, a vascular appearing lesion truly “present since birth” and presenting with a rapid increase in size or other concerning features should merit consideration of CIFS and biopsy. In addition, ulceration, fixation to surrounding tissues, and recurrent bleeding episodes in combination with an increase in size of a presumed congenital hemangioma as described by Yan and colleagues4 should merit reconsideration of this diagnosis and possible biopsy. Although this patient had no laboratory abnormalities upon presentation, it should be noted that coagulopathies have been described for both hemangiomas and CIFS. Kasabach-Merritt syndrome involving thrombocytopenic purpura may be seen in association with hemangiomas and other vascular malformations, whereas consumptive © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Annals of Plastic Surgery • Volume 74, Supplement 1, May 2015
CIFS Presenting as Hemangioma
FIGURE 2. Preoperative MRI imaging. A and B, Axial views. C and D, Sagittal views. B and C, T1-weighted images; A and D, T2-weighted images.
coagulopathy and disseminated intravascular coagulation may be a sign of malignancy and CIFS, and the 2 may be difficult to distinguish.8 Several case reports describe a large vascular lesion present at birth with coagulopathy initially thought to be Kasabach-Merritt associated with hemangioma, but in actuality, with manifestation of consumptive coagulopathy in conjunction with diagnosis of CIFS, diagnosed as disseminated intravascular coagulation associated with malignancy.9–11,13 Several of these authors also report a delay in diagnosis resulting in treatment of the lesion with corticosteroids as would be appropriate therapy for hemangioma with associated Kasabach-Merritt phenomenon, with diagnosis on biopsy after failure of the lesion to respond. On physical examination, some authors have noted subtle differences that may be useful in differentiating hemangiomas and CIFS; hemangiomas are reported as compressible and soft, whereas the tumor in CIFS is more firm and shiny in appearance.11,13 However, biopsy remains essential in diagnosis of CIFS and differentiation from atypical hemangioma or other vascular malformation, with immunohistochemistry for fibrosarcoma markers (vimentin positive, S100 negative) and RT-PCR for the ETV6-NTRK3 gene product to further aid in confirming the diagnosis. Although the histologic appearance of the tumor in this case was consistent with CIFS, it was atypical in that RT-PCR for ETV6-NTRK3 was negative, and the tumor was positive for CD34 in addition to vimentin on immunohistochemistry. Although vimentin is essentially positive in all fibrosarcomas, CD34 is less common but still consistent with this diagnosis.16 The t(12;15)(p12;q25) translocation has been noted to be present in most, but not all cases of © 2015 Wolters Kluwer Health, Inc. All rights reserved.
CIFS, and the ETV6-NTRK3 product has been noted as a key marker for differentiation of CIFS from other spindle cell tumors of childhood.5,16,17 Because of these unusual findings, the patient's tumor was sent for a second opinion, at which time dermatofibrosarcoma protuberans was suggested; however, the tumor was also negative for the platelet-derived growth factor receptor-beta rearrangement associated with this diagnosis. McCahon and colleagues18 have suggested that the presence of the ETV6-NTRK3 gene product may contribute to the chemosensitivity of these tumors; although this patient's response to chemotherapy remains to be determined, his unusual pathologic characteristics illustrate the difficulty in attaining a definitive diagnosis that may be used to guide therapeutics and assess treatment efficacy. Although imaging is useful in assessing the extent of the lesion, as this case demonstrates and several reports in the literature have confirmed, imaging findings in the case of CIFS and most of soft tissue tumors are nonspecific. Magnetic resonance imaging findings in CIFS typically include a well-circumscribed mass that is isointense to muscle on T1-weighted imaging and hyperintense on T2-weighted sequences, and larger tumors may demonstrate associated hemorrhage.19,20 When CIFS is confirmed, MRI is most useful for assessing soft tissue, vascular, and neural invasion to aid in treatment and surgical planning as well as for surveillance for disease recurrence after resection; CT is recommended if there is concern for bony involvement.6 Wide local excision remains the standard of care for treatment of CIFS, and children in whom negative margins are achieved may be observed without adjuvant radiation or chemotherapy.7 Therefore, www.annalsplasticsurgery.com
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Annals of Plastic Surgery • Volume 74, Supplement 1, May 2015
Kanack et al
primary surgical excision alone.25 Metastasis is rare, although with a higher rate of 26% reported in patients with axial primaries compared to 8% in those with extremity primaries.25 The lungs are the most frequent site of metastasis, with bone, brain, and adrenal glands as other reported metastatic sites.22 Although there are few reported data on the timing of metastasis, the patient in this report was at increased risk given the location of his primary tumor, and the rapid evolution of his recurrence and metastasis over 9 months after complete resection with negative margins emphasizes the importance of frequent surveillance in patients treated primarily with surgery.
CONCLUSIONS Congenital-infantile fibrosarcoma may mimic an atypical, ulcerated congenital or infantile hemangioma upon presentation, which has prognostic implications due to the potential for delay in diagnosis and thus initiation of appropriate treatment. In addition to initial presentation as an ulcerated hemangioma, this case also demonstrates a less common axial location of the tumor, atypical pathology, and metastatic and recurrent disease 9 months after initial resection. In particular, this serves to illustrate the complicated nature of these cases and emphasizes the high index of suspicion necessary in assessing an atypical lesion resembling a vascular malformation to make a rapid and correct diagnosis of CIFS. Further, this case demonstrates the important role of close surveillance in patients treated with excision as initial therapy for detection of disease recurrence and metastasis. REFERENCES
FIGURE 3. Pathologic specimen demonstrating dense proliferation of spindle cells in a herringbone pattern; the specimen also displayed a mitotic rate of up to 10 mitotic figures per high-power field.
lesions that could potentially be CIFS should be removed in a manner that will facilitate wide local excision with negative margins if needed. However, in the case of large lesions, especially those located on the distal extremities, use of neoadjuvant chemotherapy has been reported to decrease tumor bulk and thus reduce the need for amputation and enable a more conservative surgical approach.21 One case has been reported of a CIFS of the foot that resolved completely with chemotherapy, allowing the limb to be spared and emphasizing the chemosensitive nature of this tumor.22 Common chemotherapeutic regimens include vincristine, cyclophosphamide, and either adriamycin or actinomycin-D.23 Although radiation is not typically used in treatment of CIFS, it has been reported for emergent tracheal decompression in one case as well as in select cases with metastatic and recurrent disease.23 Compared to fibrosarcoma in adults as well as other aggressive spindle cell sarcomas of childhood, prognosis is generally viewed as good, with a 5-year survival rate of 84% in a case study of 85 patients.24 Local recurrence has been reported at a rate of 17% to 43% after S28
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1. Tarik E, Abdelouahed A, Tarik M, et al. Unusual case of congenital/infantile fibrosarcoma in a new born. Afr J Paediatr Surg. 2013;10:185. 2. Requena C, Miranda L, Cañete A, et al. Congenital fibrosarcoma simulating congenital hemangioma. Pediatr Dermatol. 2008;25:141–144. 3. Chen TS, Eichenfield LF, Friedlander SF. Infantile hemangiomas: an update on pathogenesis and therapy. Pediatrics. 2013;131:99–108. 4. Yan AC, Chamlin SL, Liang MG, et al. Congenital infantile fibrosarcoma: a masquerader of ulcerated hemangioma. Pediatr Dermatol. 2006;23:330–334. 5. Sheng WQ, Hisaoka M, Okamoto S, et al. Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6NTRK3 fusion transcripts using paraffin-embedded tissues. Am J Clin Pathol. 2001;115:348–355. 6. Braun P, Fernández-Montes JG, Calatayud AV. Congenital infantile fibrosarcoma: report of four cases and review of the literature. Eur J Radiol Extra. 2007;61: 33–39. 7. Cofer BR, Vescio PJ, Wiener ES. Infantile fibrosarcoma: complete excision is the appropriate treatment. Ann Surg Oncol. 1996;3:159–161. 8. Kerl K, Nowacki M, Leuschner I, et al. Infantile fibrosarcoma—an important differential diagnosis of congenital vascular tumors. Pediatr Hematol Oncol. 2012; 29:545–548. 9. Asgari M, Rubin BP, Hornung RL. Neonate with a fibrosarcoma and consumptive coagulopathy. J Am Acad Dermatol. 2004;50:23–25. 10. Muzaffar AR, Friedrich JB, Lu KK, et al. Infantile fibrosarcoma of the hand associated with coagulopathy. Plast Reconstr Surg. 2006;117:81e–86e. 11. Boon LM, Fishman SJ, Lund DP, et al. Congenital fibrosarcoma masquerading as congenital hemangioma: report of two cases. J Pediatr Surg. 1995;30: 1378–1381. 12. Akyuz C, Kupeli S, Varan A, et al. Infantile fibrosarcoma: retrospective analysis of eleven patients. Tumori. 2011;97:166–169. 13. Hayek SN, Janom HH, Ibrahim A, et al. Infantile fibrosarcoma misdiagnosed as vascular tumors. Hand. 2013;8:464–468. 14. Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting congenital hemangioma: clinical and histopathologic features. Pediatr Dev Pathol. 2003;6:495–510. 15. Konez O, Burrows PE, Mulliken JB, et al. Angiographic features of rapidly involuting congenital hemangioma (RICH). Pediatr Radiol. 2003;33:15–19. 16. Bourgeois JM, Knezevich SR, Mathers JA, et al. 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. 17. Guillou L, Folpe AL. Fibroblastic and fibrohistiocytic tumors. In: Folpe AL, Inwards CYeds. Bone and Soft Tissue Pathology. Philadelphia, PA; Churchill Livingston; 2010:43–96.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Annals of Plastic Surgery • Volume 74, Supplement 1, May 2015
18. McCahon E, Sorensen PH, Davis JH, et al. Non‐resectable congenital tumors with the ETV6–NTRK3 gene fusion are highly responsive to chemotherapy. Med Pediatr Oncol. 2003;40:288–292. 19. Canale S, Vanel D, Couanet D, et al. Infantile fibrosarcoma: magnetic resonance imaging findings in six cases. Eur J Radiol. 2009;72:30–37. 20. Ainsworth KE, Chavhan GB, Gupta AA, et al. Congenital infantile fibrosarcoma: review of imaging features. Pediatr Radiol. 2014;44:1124–1129. 21. Mnif H, Zrig M, Maazoun K, et al. Congenital infantile fibrosarcoma of the forearm. Chir Main. 2011;30:148–151.
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CIFS Presenting as Hemangioma
22. Demir HA, Akyüz C, Varan A, et al. Right foot congenital infantile fibrosarcoma treated only with chemotherapy. Pediatr Blood Cancer. 2010;54:618–620. 23. Loh ML, Ahn P, Perez-Atayde AR, et al. 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. 24. Chung E, Enzinger FM. Infantile fibrosarcoma. Cancer. 1976;38:729–739. 25. Shetty AK, Yu LC, Gardner RV, et al. Role of chemotherapy in the treatment of infantile fibrosarcoma. Med Pediatr Oncol. 1999;33:425–427.
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