IJSXXX10.1177/1066896914537682International Journal of Surgical PathologyCaffrey et al

Case Report

Metachronous Myxofibrosarcoma and Osteosarcoma: Case Report and Review of the Literature

International Journal of Surgical Pathology 2015, Vol. 23(2) 149­–155 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914537682 ijs.sagepub.com

Rachael Caffrey, MbBCh1, Andrew J. Robinson, MbBCh1, Satyen Shukla, FRCR1, Heather McCarty, MRCP, FRCR2, Alastair Brown, FRCS1, and Oisín P. Houghton, FRCPath3

Abstract The occurrence of multiple primary sarcomas in one individual is very uncommon and the development of osteosarcoma as a second tumor following a soft tissue sarcoma is extremely rare. We report a case of a 62-year-old man who developed 2 histologically distinct sarcomas: a soft tissue myxofibrosarcoma and vertebral osteosarcoma. This unusual case highlights the critical role of careful histopathological evaluation in distinguishing synchronous or metachronous neoplasia from metastatic tumor. To the best of the authors’ knowledge, this is the first reported case of metachronous soft tissue myxofibrosarcoma and osteosarcoma. Keywords sarcoma, osteosarcoma, myxofibrosarcoma, synchronous neoplasia, synchronous sarcomas, multiple sarcomas

Introduction Myxofibrosarcoma is one of the most common soft tissue sarcomas in adults1,2 and osteosarcoma is the most common primary malignant bone tumor.3,4 The occurrence of 2 histologically distinct sarcomas in 1 patient is very unusual. Only a limited number of well-described examples of morphologically distinct synchronous or metachronous soft tissue sarcomas have been published5-13 and very few examples of synchronous or metachronous soft tissue sarcoma and osteosarcoma are documented in the literature.14-18 In this report, we describe a case of metachronous soft tissue myxofibrosarcoma and vertebral osteosarcoma.

Case Report A 62-year-old man presented with a 6-month history of a gradually enlarging, painless mass in his left forearm and clinical examination revealed a 4-cm diameter mass fixed to underlying musculature. Ultrasound scan identified a mixed echogenic lesion in the flexor aspect of the left forearm, with internal vascularity. Magnetic resonance imaging demonstrated a 4.2 × 2.5 × 2.2 cm mass within the flexor carpii ulnaris muscle (Figure 1A and B). Core biopsy was performed and histological examination showed a spindle cell sarcoma with fibroblastic–myofibroblastic differentiation.

The mass was surgically excised. The soft tissue resection measured 85 × 40 × 26 mm and sectioning revealed a well-circumscribed homogeneous tan-white colored tumor measuring 29 × 23 × 18 mm, with a firm and focally myxoid cut surface. Histological examination showed a tumor of moderate cellularity, composed of spindle cells with mild and focal moderate cytologic atypia (Figure 2A-C). The cells were set in a variably fibromyxoid stromal background and there were conspicuous curvilinear thin-walled blood vessels. Areas with greater cellularity, a fascicular and storiform architecture, and more pronounced cytologic atypia were present. In these areas, numerous mitoses (10 per 10 high-power fields) were seen. There was no giant cell population, matrix production, necrosis, or vascular invasion. The tumor was marginally excised. Immunohistochemical staining shows focal positivity for SMA and CD34. Desmin, AE1/AE3, and S100 were negative. The morphologic and immunophenotypic features were of a grade 2 myxofibrosarcoma.


The Ulster Hospital, Belfast, Northern Ireland Northern Ireland Cancer Center, Belfast, Northern Ireland 3 Royal Group of Hospitals, Belfast, Northern Ireland 2

Corresponding Author: Oisín P. Houghton, Department of Pathology, Royal Group of Hospitals Trust, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland. Email: [email protected]


International Journal of Surgical Pathology 23(2)

Figure 1.  (A) An axial T2-weighted magnetic resonance image (MRI) of the left forearm showing the soft tissue myxofibrosarcoma (→) within the flexor carpii ulnaris muscle. (B) An axial T2-weighted MRI with fat suppression showing the soft tissue myxofibrosarcoma (→). (C) A sagittal T2-weighted MRI of thoracolumbar spine showing the vertebral osteosarcoma (→) with destruction of the posterior elements of the T12 vertebra.

Postoperatively, he received radiotherapy to the left forearm with 55 Gy in 25 fractions over 5 weeks. He was treated with a parallel pair of 6 megavoltage photons and was reviewed at 3-month intervals with regular chest x-rays to exclude pulmonary metastasis. At his 2-year review, he complained of a 3-month history of mid back pain. The back pain was localized to both flanks but did not radiate. It was also associated with the onset of an intermittent cough for 3 months. There were no bladder, bowel, or lower leg symptoms and chest, neurological and rectal examination was unremarkable. X-ray showed a mild narrowing of the L5-S1 disc space with generalized osteoarthritic changes seen throughout, but no intraparenchymal lung mass. However, computed tomography scan identified an osteolytic lesion, measuring 21 × 16 × 13 mm, involving both laminae and the spinous process of T12 with soft tissue extension and protrusion into the central spinal. The most likely radiologic diagnosis was a spinal metastasis. Magnetic resonance imaging scan of the whole spine supported the probable diagnosis of a metastatic deposit in the posterior elements of T12, with bony destruction and extension into the spinal canal (Figure 1C). There was no compression of the spinal cord or nerve roots. Following multidisciplinary discussion, en bloc resection of the T12 mass and posterior stabilization of his spine from T10 to L2 was performed. Intraoperatively, the tumor mass was attached to the dura of the spinal cord and involved the pedicles and posterior elements of T12. Complete removal of the mass from the dura was not possible as it was adherent to the spinal cord. The resection from the T12 vertebra was received as several fragments of bony tissue, in aggregate measuring 70 × 65 × 30 mm. Histopathological examination showed

a sarcoma which was morphologically distinct from the soft tissue myxofibrosarcoma (Figure 2D-F). The tumor was composed of pleomorphic oval to spindle-shaped cells with numerous admixed osteoclast-like tumor giant cells. Mitoses, including atypical forms, were easily identified. There was also conspicuous osteoid production by tumor cells, which was mostly sheet-like but in areas had a lacelike pattern. The tumor permeated the marrow space and encased preexisting cancellous bone. Overall, the appearances were of a high-grade conventional osteosarcoma, giant cell–rich subtype. He had a comfortable postoperative period with no complications or neurological upset. The patient received post operative radiotherapy. However, 6 months following surgery, he was found to have local tumor recurrence in his thoracolumbar spine invading into the adjacent paraspinal musculature. He died 1 month later.

Discussion To our knowledge, this case is the first report of metachronous myxofibrosarcoma and osteosarcoma. The soft tissue tumor exhibited the characteristic morphologic features of myxofibrosarcoma with a variably fibromyxoid stroma and conspicuous curvilinear vascular channels. Its immunoprofile was nonspecific, but consistent with a tumor of fibroblastic–myofibroblastic lineage. In contrast, the vertebral tumor exhibited features characteristic of a highgrade conventional osteosarcoma, with pleomorphic oval- to spindle-shaped cells and frequent osteoclast-like tumor giant cells, in addition to conspicuous osteoid production. Myxofibrosarcoma is one of the most common soft tissue sarcomas in adults, occurring principally in

Caffrey et al


Figure 2.  (A-C) Soft tissue myxofibrosarcoma. (A) Low- to intermediate-grade regions with variably fibromyxoid stroma and curvilinear vessls. (B) Low-grade area with mild cytologic atypia, characteristic thin-walled curvilinear vessels and mild cytologic atypia. (C) Zone with fascicular and focal storiform architecture, high cellularity, and moderate to marked cytologic atypia. (D-F) Vertebral osteosarcoma. (D) Osteosarcoma infiltrating the marrow and encasing preexisting cancellous bone (→) with deposition of osteoid (). (E) Giant cell–rich region with numerous nonneoplastic osteoclast-like giant cells. Note the “normalization” of tumor cells trapped within matrix (), which exhibit only mild cytologic atypia. (F) Giant cell–rich area with numerous osteoclastlike giant cells admixed with severely atypical oval- and spindle-shaped tumor cells.

elderly patients. It occurs more often in males than females with the majority of cases arising in the limbs, more frequently in the lower extremities than the upper extremities.1,2 Osteosarcoma is the most common primary malignant bone tumor. Although it is more common in children and young adults, 30% of cases arise in patients older than 40 years.19 Most tumors arise in long tubular bones; however, an origin in any bone is possible and spinal osteosarcoma tends to occur in older adults.20 The etiology is unclear, but there is an increased

incidence in genetic disorders such as Li-Fraumeni21 and Rothmund-Thomson syndrome.22 Secondary osteosarcoma occurs more often in older patients, for example, arising in bone affected by Paget’s disease or infarction.23 It can also occur in bones previously exposed to radiotherapy and it is the most common radiation-induced sarcoma.24 Although synchronous or metachronous neoplasia is not uncommon, the occurrence of histologically distinct synchronous or metachronous sarcomas is very unusual.

152 Histologically distinct synchronous or metachronous sarcomas, including synchronous soft tissue sarcoma and osteosarcoma, have been reported in several studies.5-18,25-32 To the best of our knowledge, however, only 24 welldescribed examples of histologically distinct synchronous or metachronous sarcomas have been published. These include 18 examples of synchronous or metachronous soft tissue sarcomas5-13 and 6 examples of synchronous or metachronous soft tissue sarcoma and osteosarcoma14-18 (Table 1). Ten of these previously published patients were single case reports. Eight of the remaining 14 were reported in the largest published series of multiple primary soft tissue sarcomas,9 2 were part of a large series of patients with soft tissue sarcomas that developed various second malignancies,7 2 were from a genetic study of sarcoma-prone families,16 and 1 was from a series of gastrointestinal stromal tumors with a range of other synchronous or metachronous tumors.11 Notably, Grobmyer et al9 included in their series a case of liposarcoma and metachronous endometrial malignant mixed mullerian tumor. We feel that this case should not be considered an example of metachronous sarcoma as malignant mixed mullerian tumor is a carcinoma with sarcomatous differentiation and not a mesenchymal tumor. The previously reported cases include 9 males and 12 females. Sex was not stated in 3 cases. The median age of patients with synchronous or metachronous soft tissue sarcoma was 56 years. The median age of patients with synchronous or metachronous soft tissue sarcoma and osteosarcoma was considerably younger at 24 years, which is presumably explained by the typical young age of presentation of most osteosarcomas. Five of the 6 patients with synchronous or metachronous osteosarcoma and soft tissue sarcoma presented with osteosarcoma as the initial sarcoma. Overall, the patients had a median age of 47 years (range 9-81 years). The age at diagnosis was not stated in 2 cases. The interval to the second tumor was known in 22 cases and the median interval was 53 months (range 0-336 months). The most frequent combinations of mesenchymal tumors were gastrointestinal stromal tumor and liposarcoma (4 cases)9,13 and leiomyosarcoma and liposarcoma (3 cases).8-10 The soft tissue tumors synchronous or metachronous to osteosarcoma were Ewing sarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma, and inflammatory pseudotumor.14-18 When a second tumor arises, often the initial clinical suspicion is of recurrent or metastatic tumor. In this case, the second tumor was suspected clinically and radiologically to be a metastasis, which is not surprising as the soft tissue myxofibrosarcoma was grade 2, a tumor

International Journal of Surgical Pathology 23(2) with significant metastatic potential. Intermediate- and high-grade myxofibrosarcomas develop metastases in 20% to 35% of cases.2 Imaging of the vertebral tumor showed no radiologic evidence of mineralization, and an osteoblastic neoplasm was not considered in the radiologic differential. Crucially, the second neoplasm was biopsied and morphological evaluation revealed 2 histologically distinct tumors. There are several potential explanations for the occurrence of synchronous or metachronous sarcomas. Possible reasons include genetic predisposition, impaired immune state, or previous exposure to mutagenic therapies such as chemotherapy or radiotherapy. In some genetic syndromes, such as Li-Fraumeni syndrome where there is a germline mutation in the TP53 tumor suppressor gene,33 patients are at risk of multiple malignancies. Chemotherapy is also thought to increase the risk of synchronous malignancy and the risk is even greater if multiple chemotherapeutic agents have been used.34 In addition, as stated above, it is well recognized that previous radiotherapy increases the risk of secondary osteosarcoma. The risk of osteosarcoma following radiation therapy is thought to be dose dependent with greater susceptibility following a radiation dose greater than 20 Gy.35,36 There are clearly identifiable risk factors for the occurrence of a second malignancy in the previously reported well-described cases of synchronous or metachronous osteosarcoma and soft tissue sarcoma. Two patients with Li-Fraumeni syndrome developed soft tissue sarcoma (liposarcoma and rhabdomyosarcoma) following osteosarcoma,15 3 patients developed soft tissue sarcomas (synovial sarcoma, Ewing sarcoma, and leiomyosarcoma) following chemotherapy treated osteosarcoma,14,16,18 and 1 patient’s osteosarcoma followed radiotherapy for an inflammatory pseudotumor.14 The etiology of metachronous neoplasia, however, in this case is unclear. The patient did not fulfill the required clinical diagnostic criteria for a predisposing genetic syndrome such as Li-Fraumeni syndrome and his first sarcoma was not treated with chemotherapy. While he did receive postoperative radiotherapy for the soft tissue myxofibrosarcoma, any possible oncogenic effect would probably have been minimal as the field of radiation exposure in the left forearm is a considerable distance from the 12th thoracic vertebra. Although one could speculate that impaired immune status with advancing age may have played a role, the definitive etiology is unknown. In summary, this report describes the extremely unusual occurrence of metachronous soft tissue sarcoma and osteosarcoma. It emphasizes the importance of considering the possibility of a new primary and the critical role of biopsy and accurate histopathological evaluation


Caffrey et al Table 1.  Prior Well-Described Reports of Synchronous or Metachronous Histologically Distinct Sarcomas.5-18 Age (Years)/ Sex 44/Female 51/Female Unknowna,b Malea 70/Female 77/Male 55/Female 51/Female

Primary Sarcoma Malignant fibrous histiocytoma (left thigh) Leiomyosarcoma (liver) Meningiosarcoma (frontal lobe) Rhabdomyosarcoma (paratesticular) Well-differentiated liposarcoma (retoperitoneum) Dedifferentiated liposarcoma (extremity) GIST


Well-differentiated liposarcoma (extremity) Kaposi sarcoma (extremity) Liposarcoma (extremity) Dermatofibrosarcoma protuberans (chest wall) Dermatofibrosarcoma protuberans (extremity) Synovial sarcoma (extremity) Leiomyosarcoma (uterus)

10/Female 71b 58b 56/Male

Neuroblastoma (adrenal) GIST GIST Leiomyosarcoma


Osteosarcoma (tibia)

59/Female 22/Male 22/Male 23/Male

Inflammatory pseudotumor (oral mucosa) Osteosarcoma Osteosarcoma Osteosarcoma (fibula)



74/Male 81/Male 68/Female 56/Female 51/Male

Interval to Second Sarcoma

Second Sarcoma



Myxoid liposarcoma (Left lower leg) Angiosarcoma (spleen) Liposarcoma (thigh)

1 mo


Kulman et al


A + W 36 mo

Kinoshita et al

180 mo

A + W 199 mo

Merimsky et al

Malignant fibrous histiocytoma (abdominal wall) Leiomyosarcoma (retroperitoneum)

144 mo

A + W 247 mo

Merimsky et al

39 mo

DOD 24 mo

Aurello et al



A + W 12 mo

Grobmyer et al

Well-differentiated liposarcoma (extremity) Leiomyosarcoma (retroperitoneum) Fibrosarcoma (extremity) GIST GIST

3 mo

A + W 12 mo

Grobmyer et al


A + W 2 mo

Grobmyer et al

72 mo

DOD 84 mo

Grobmyer et al

60 mo 12 mo

A + W 84 mo A + W 18 mo

Grobmyer et al Grobmyer et al

Solitary fibrous tumor (spine) GIST

6 mo

A + W 6 mo

Grobmyer et al

132 mo

AWD 62 mo

Grobmyer et al

Well-differentiated liposarcoma (retroperitoneum) GIST Liposarcoma Kaposi sarcoma GIST


A + W 11 mo

Chen et al

111 mo Unknown Synchronous Synchronous

Goncalves Ponti et al Ponti et al Sevinc et al

45 mo

A + W 59 mo Unknown Unknown A + W (unknown period) A + W 40 mo

336 mo


Onodera et al

Unknown 60 mo 24 mo

Unknown Unknown A + W 40 mo

Lynch et al Lynch et al Kudawara et al

48 mo

A + W 108 mo

Stebnicky et al

Leiomyosarcoma (small intestine) Osteosarcoma (mandible) Liposarcoma Rhabdomyosarcoma Synovial sarcoma (knee) Ewing sarcoma

Craft et al

Abbreviations: GIST, gastrointestinal stromal tumor; A + W, alive and well; AWD, alive with disease; DOD died of disease. a Age not stated. b Sex not stated.

when a second tumor arises. To the best of our knowledge, this is the first report of soft tissue myxofibrosarcoma and vertebral osteosarcoma occurring in one individual.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

154 Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Metachronous myxofibrosarcoma and osteosarcoma: case report and review of the literature.

The occurrence of multiple primary sarcomas in one individual is very uncommon and the development of osteosarcoma as a second tumor following a soft ...
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