Case12
Congenital/ infantile Fibrosarcoma

History
Male fetus at the 23rd week of gestation. Abortion induced because of a large left
thigh tumour.

Pathology
The tumour of the left thigh weighed 194 g (fetal weight 787.40g) and measured 9.5 x 8
x 6.5 cm. Destruction of femoral bone was demonstrated by radiograph and on cut section.
Otherwise, fetal organ development corresponded to 25th week of gestation. There was a Meckel diverticulum of 8mm length, 18cm before the ileocoecal valve, without inclusion of heterotopic gastric tissue.

Discussion
Although congenital or infantile fibrosarcoma is comparatively rare, it is the foremost
sarcoma of the newborn. It was first studied in detail by Stout in 1962. In 1976, Chung and Enzinger supported Stout’s separation of this entity from the adult counterpart. Even if fibrosarcoma in infancy and young children bears a close morphologic resemblance to adult fibrosarcoma, it must be considered as a separate entity because of its markedly different clinical behaviour with more favourable prognosis. Similarly, in contrast to adult fibrosarcoma, infantile fibrosarcoma affects the more distal portions of the extremities rather than proximal extremities or trunk.

Up to 30% are present at birth. Most tumours are evident within the first year of life.

The principal manifestation is a painless swelling with steady, sometimes rapid growth. Males are affected slightly more common than females. The distal extremities are the sites principally involved, followed by the trunk, head and neck. Nevertheless, rare tumours may occur in the mesentery, retroperitoneum and orbit. Radiographic examination may reveal cortical thickening, bending deformities or rarely more extensive destruction of the underlying bone, as in the present case.

Macroscopically, tumour size varies considerably from a few centimeters to replacement of the entire distal limb portion. Large exophytic masses may lead to skin ulceration. Tumours are usually poorly circumscribed with a gray white or pink cut surface. Central necrosis or hemorrhage may be prominent, as well as myxoid or cystic change.

Microscopically, congenital fibrosarcoma is composed of sheets of closely packed uniform, monomorphous spindle-shaped cells arranged in bundles and fascicles, resulting in a herringbone pattern. Mitotic figures may be frequent in some tumour regions. Some tumours show abundant collagen production and more fasciculation, similar to adult fibrosarcoma, whereas others consist of more rounded immature-appearing cells with only focal evidence of fibroblastic differentiation. Dahl separated the former as ‘desmoplastic’ type from the latter ‘medullary’ type. Similar to adult fibrosarcoma, giant cells are rare, but in contrast to adult fibrosarcoma, scattered chronicinflammatory cells are a common, characteristic feature of infantile fibrosarcoma. Some areas may be quite vascular.

Immunohistochemistry and ultrastructure demonstrate the fibroblastic and myofibroblastic nature of the tumour cells with expression of vimentin, muscle-specific and smooth muscle actin in the more mature and differentiated cells. Desmin and Myoglobin are generally negative.
Cytogenetic findings are unique in infantile fibrosarcoma: former studies have shown a non-random gain of chromosomes 11, 20, 17 and 8 in infantile fibrosarcoma. More recently, it has been found that most infantile fibrosarcomas and cellular mesoblastic nephromas share the same diagnostic chromosomal translocation: t(12;15)(q13;q25). This translocation results in fusion of the ETV6 gene, also known as TEL on chromosome 12 with the neurotrophin-3 receptor NTRK3, also known as TRKC, gene on chromosome 15. The translocation can readily be demonstrated by RT-PCR or FISH on frozen or paraffin-embedded tissue.
Deletions of the short arm of chromosome 17 and a translocation t(12;13) have been other
cytogenetic abnormalities noted in congenital fibrosarcoma.
The differential diagnosis includes spindle cell rhabdomyosarcoma, infantile
rhabdomyofibrosarcoma, infantile hemangiopericytoma and infantile fibromatosis.

Spindle cell rhabdomyosarcoma as a subtype of embryonal rhabdomyosarcoma occurs in the paratesticular region, head and neck, but may also occur in the extremities. It is composed of spindle cells with eosinophilic fibrillary cytoplasm. It characteristically expresses desmin, which is usually absent in infantile fibrosarcoma.

Infantile rhabdomyofibrosarcoma might represent an intermediate form between infantile
fibrosarcoma and spindle cell rhabdomyosarcoma. It is a recently described tumour with features of spindle cell rhabdomyosarcoma and desmoplastic portions reminiscent of infantile fibrosarcoma. It occurred in three patients between 3 months and 3 years of age. Immunohistochemically, tumour cells express desmin but are negative for myoglobin. Cytogenetics showed monosomy of chromosomes 19 and 20, and der (2) t 2;11)(q37;q13). The clinical course was aggressive with death of metastatic disease in two of the three patients, and local recurrence in the third.

In case of marked vascularity, infantile fibrosarcoma may be difficult to distinguish from infantile hemangiopericytoma, but lacks the latter’s distinct lobulated arrangement and more regularly distributed vascular channels forming a ‘staghorn’ pattern.

Distinction from infantile fibromatosis requires attention to the following criteria: in infantile
fibromatosis, cellularity varies, a herringbone pattern is usually absent, mitotic figures are rare, hemorrhage and necrosis are absent, and there are no characteristic cytogenetic abnormalities. In contrast, in infantile fibrosarcoma, cellularity is moderate to high, a herringbone pattern is usually present, mitotic figures are frequent, hemorrhage and necrosis are often present, and a characteristic karyotype is found.

Wide local excision is the treatment of choice, even if for some large tumours amputation may be necessary as a last resort. Since extensions of tumour blend subtly with the adjacent soft tissues, ‘shelling out’ leaves residual tumour behind. Therefore, wide local excision is required, preferably at the initial surgery, if this is technically feasible. Adjuvant chemotherapy is recommended for those patients with unresectable tumours of axial skeleton and proximal extremities.

Excepting local aggressiveness, the clinical course of congenital-infantile fibrosarcoma is favourable, compared with adult fibrosarcoma. Local recurrences occured in 17% to 32% of patients 6 weeks to 10 years after the initial excision. The incidence of distant metastasis is higher for axial tumours than for those of the extremities: 26% and 8%, respectively. The five-year survival rate was 84 % in the series by Chung and Enzinger, overall survival is currently estimated as higher than 90%, compared to a 5-year survival rate of 50% in adult fibrosarcoma. Including most recent investigations, recurrence and metastatic rate depended on the completeness and extent of local resection. Most studies have found that cellularity, mitotic counts and extent of necrosis do not correlate well with clinical behaviour, in contrast to Dahl’s series with a more favourable prognosis for the ‘medullary’ than the ‘desmoplastic’ type. There are some sporadic reports of spontaneous regression.

As a consequence of histologic and cytogenetic similarity, it has been suggested, that congenital fiibrosarcoma and cellular congenital mesoblastic nephroma represent histogenetically related entities arising in soft tissue or kidney, respectively. There are no definite hereditary diseases or congenital malformations associated with this malignant tumour.

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