History
7-year-old girl with a large (13x10 cm) tumor on the left side
of the thorax, just below the scapula.
Pathology
Loose mesenchymal tissue with a rich vasculature and large spindle
cells with plump
nuclei; many mitoses and many infiltrating mast cells. The spindle
cells stain positive for vimentin and smooth muscle actin, they
are negative for desmin, S-100 and CD34. Proliferation index
(MIB- 1) is about 80%.
Discussion
Fibrodysplasia ossificans progressiva (FOP) is a rare
genetic disorder (MIM 135100) consisting of progressive heterotopic
ossification associated with dysregulated production of bone
morphogenetic protein 4 (BMP4). The disease is heralded by
congenital hallux valgus (Fig. A). During the first years of
life, traumas (even minor), leading to connective tissue swelling
and intramuscular edema, are followed by the formation of a
highly angiogenic fibroproliferative tissue, which entraps
muscle (Fig. B) with subsequent muscle necrosis (arrows on muscle
fibre residues in Fig. C). Later on (not seen in this case),
fibrous tissue differentiates into cartilage (cells express S100),
which undergoes the normal sequential changes of enchondral ossification,
the most common locations being neck, shoulders, back and rib
cage. (Fig. D,E). Without knowledge of the congenital hallux
valgus, the differential diagnosis would be nodular fasciitis
(which has interweaving fascicles) and, after ossification has
started, myositis ossificans (which has a zonation pattern).
Inflammatory pseudotumor rarely occurs in the integument and
has a mixed lympho-plasmacytic infiltrate.
FOP is transmitted as a dominant trait with variable expression.
Due to the disabling nature of the disease, most observed cases
occur “sporadically” because they represent new mutations.
The gene for FOP has been localized to chromosome 17q22. A candidate
gene is NOG which codes for the BMP4 inactivating polypeptid
Noggin (no mutations having been identified in the BMP4 gene
itself). There is only one affected patient for every 2 million
population, with no sexual, racial or ethnic predilection. Most
patients are confined to a wheel chair by the third decade of
life and
succumb to pulmonary complications in the fifth decade. Patients
are advised to avoid trauma, especially that iatrogenically delivered
in the form of intramuscular injection and surgery. There are
trials of drug treatment with steroids or retinoids (which inhibit
differentiation of mesenchymal tissue into cartilage and bone).
Progressive osseous heteroplasia (POH) is another autosomal dominant
disorder (MIM 166350) which features heterotopic ossification.
It is distinct from FOP, in that bone formation starts in the
reticular dermis and subcutaneous fat and is not associated with
trauma. The ossified areas coalesce and may later invade fascia
and skeletal muscle.
