Soft Tissue Pathology
Moderators: Dr. John R. Goldblum and Dr. Cyril Fisher
Case 4 -
Phosphaturic mesenchymal tumor, mixed connective tissue type, histologically and clinically malignant
Andrew L. Folpe, M.D.
Department of Laboratory Medicine and Pathology
Mayo Clinic, Rochester , MN USA
A 50 year old male presented with a recurrent, destructive lesion of the mandible. His clinical
history was significant for long-standing hypophosphatemic osteomalacia. Approximately 12 months ago he
noticed a mass in his oral cavity; that tumor was resected 7 months before the resection of this
Case 4 - Slide 1
The primary tumor was highly cellular and infiltrative, and consisted of an admixture of
hyperchromatic ovoid to spindled cells, innumerable osteoclast-like giant cells, woven bone, and an
unusual-appearing, calcified matrix. Mitotic figures were frequent. The recurrent tumor was generally
similar to the primary lesion, but showed in addition foci of coagulative tumor cell necrosis.
Phosphaturic mesenchymal tumor, mixed connective tissue type, histologically and clinically malignant.
Osteomalacia, a metabolic bone disorder resulting from inadequate mineralization of osteoid in mature
bone, has a remarkably diverse etiology, ranging from rare inborn errors of metabolism such as autosomal
dominant hypophosphatemic rickets and X-linked hypophosphatemic rickets to more common processes, such as
chronic renal disease. One of the most unusual types of osteomalacia is oncogenic osteomalacia (OO), in
which systemic bone demineralization is caused by, and may be cured by resection of a neoplasm. OO is
characterized clinically by bone pain and fractures, renal phosphate wasting, hypophosphatemia, decreased
serum 1,25-dihydroxyvitamin D3 levels and resistance to vitamin D supplementation.
McCance is traditionally credited with reporting the first case of OO, although he did not recognize
the tumor as the cause of osteomalacia. Prader and colleagues were the first to recognize a neoplasm as
the cause of osteomalacia, in their 1957 report of a putative giant cell reparative granuloma of the rib.
Subsequently, more than 100 cases of OO have been reported, almost always in the context of case reports
or very small series. Although was initially thought that essentially any soft tissue or bone tumor
could give rise to osteomalacia, it is now clear that these tumors in fact represent a single histologic
entity, in almost all cases. This concept was first suggested simultaneously by Evans and Azzopardi, and
Olefsky and colleagues, and was further advanced in the landmark 1987 study of Weidner and Santa Cruz,
who coined the term "phosphaturic mesenchymal tumor, mixed connective tissue variant" (PMTMCT). As
defined by Weidner and Santa Cruz, PMTMCT is characterized by an unusual admixture of spindled cells,
osteoclast-like giant cells, microcysts, prominent blood vessels, cartilage-like matrix, and metaplastic
bone. Most recently, in collaboration with a large number of other investigators, I reported an
additional 27 cases of PMTMCT, the largest series to date, further emphasizing the histologic unity of
these very rare mesenchymal neoplasms.
Histologically, PMTMCT are characterized by a highly vascular proliferation of bland, spindled to
stellate cells, which produce an unusual "smudgy" matrix. The vasculature of PMTMCT may be
hemangiopericytoma-like, or may consist simply of numerous arborizing capillaries. The matrix of PMTMCT
calcifies in a distinctive "grungy" or flocculent fashion, and may resemble primitive cartilage or
chondroid. This calcification in turn appears to serve as a stimulus for the recruitment of osteoclasts,
occasionally provokes a fibrohistiocytic reaction and/or aneurysmal bone cyst-like changes, and may
undergo osseous metaplasia. Malignant PMTMCT show frankly sarcomatous features, such as high nuclear
grade, high cellularity, necrosis and elevated mitotic activity. Such cases appear to have significant
capacity for aggressive local recurrence, distant metastasis, and adverse patient outcome.
Histologically benign PMTMCT appear to behave in a clinically benign fashion, although local recurrences
may be seen.
PMTMCT are extremely rare tumors, although their exact incidence is difficult to determine. In our
recent study, PMTMCT accounted for only 9 of roughly 150,000 mesenchymal tumors in the archives of the
AFIP Soft Tissue and Bone divisions. Most cases occur in middle-aged adults, although cases have been
reported in patients as young as 3 years and as old as 73 years. There does not appear to be a
predilection for either sex. Soft tissue and bone case each count for very close to 50% of reported
cases, with roughly 5% occurring in the craniofacial sinuses. They may involve any soft tissue or bone
site, although involvement of the extremities or appendicular skeleton is rather more common than
involvement of the trunk or axial skeleton. For unknown reasons, PMTMCT do not appear to occur in the
retroperitoneum or in parenchymal organs. Although PMTMCT may achieve large size, they more commonly
present as small, inapparent lesions that may require very careful clinical examination and radionuclide
scans for localization in some. A long history of osteomalacia is present in almost all reported cases.
Recently, the mechanism underlying PMTMCT-induced osteomalacia has become much clearer. It has been
recognized for some time that mesenchymal tumor-associated osteomalacia is resistant to high dose Vitamin
D therapy and that complete tumor resection results in a dramatic reversal of the hypophosphatemia and
hyperphosphaturia, and often striking improvement in skeletal mineralization. Conditioned media from
OO-associated mesenchymal tumors have been shown to reduce renal tubular phosphate reabsorption and
implantation of tumors into nude mice has resulted in subsequent phosphaturia. These observations have
led to the proposal that these tumors secrete a circulating phosphaturic factor, termed "phosphatonin".
Shimada and colleagues have recently shown that fibroblast growth factor-23, a gene known to be mutated
in autosomal dominant hypophosphatemic rickets, is overexpressed by PMTMCT and that implantation of FGF-23 overexpressing Chinese hamster ovary cells in mice resulted in a marked
decrease in bone mineralization. FGF-23 may be degraded by PHEX, a membrane bound endopeptidase mutated
in X-linked hypophosphatemia, and it has been suggested that OO-associated mesenchymal tumors may produce
enough FGF-23 to overwhelm native PHEX levels. It is now clear that fibroblast growth factor-23 is
"phosphatonin" in almost all cases, although other proteins such as secreted frizzled related protein 4
(sFRP-4) may also play an important role in OO. The normal role of FGF-23 and the normal cell in which
it is produced remain obscure. FGF-23 may be identified within PMTMCT by both PCR and
immunohistochemistry, further confirming its role in tumor-induced osteomalacia.
The differential diagnosis of PMTMCT is broad. Typical soft tissue hemangiopericytomas show a
uniformly distributed, thick-walled branching vasculature, contain bland round to ovoid cells, frequently
express CD34, and lack the distinctive matrix of PMTMCT. Chondromas of soft parts may show a pattern of
calcification that mimics PMTMCT and often contains osteoclast-like giant cells, but lacks the bland
spindle cells, the myxoid change and the fat seen in many PMTMCT. Giant cell tumors of bone and soft
tissue (soft tissue giant cell tumors of low malignant potential) contain innumerable osteoclasts, may
show fibrohistiocytic change and often show a shell of woven bone when they involve soft tissue.
However, they lack the distinctive spindle cells and matrix of PMTMCT. Mesenchymal chondrosarcoma is an
obviously malignant-appearing sarcoma that shows an admixture of round cells, HPC-like spindled areas and
relatively mature cartilage. Recognition of the unique histologic elements of PMTMCT, and awareness that
they may contain chondroid or osteoid-like matrix, should allow their distinction from osteosarcoma and
chondrosarcoma in bone. Similarly, recognition of areas of typical PMTMCT juxtaposed to sarcomatous foci
should allow distinction of malignant PMTMCT from other pleomorphic sarcomas, such as malignant fibrous
histiocytoma and leiomyosarcoma.
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- Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, et al. Most Osteomalacia-associated Mesenchymal Tumors Are a Single Histopathologic Entity: An Analysis of 32 Cases and a Comprehensive Review of the Literature. Am J Surg Pathol 2004;28(1):1-30.
- Kumar R. New insights into phosphate homeostasis: fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia. Curr Opin Nephrol Hypertens 2002;11(5):547-53.
- Weidner N, Santa Cruz D. Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets. Cancer 1987;59(8):1442-54.
- Weidner N. Review and update: oncogenic osteomalacia-rickets. Ultrastruct Pathol 1991;15(4-5):317-33.
- Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor- induced osteomalacia. Proc Natl Acad Sci U S A 2001;98(11):6500-5.
- Ogose A, Hotta T, Emura I, Hatano H, Inoue Y, Umezu H, et al. Recurrent malignant variant of phosphaturic mesenchymal tumor with oncogenic osteomalacia. Skeletal Radiol 2001;30(2):99-103.