Article Text
Abstract
Phosphaturic mesenchymal tumour-mixed connective tissue variant is a rare tumour classically associated with oncogenic osteomalacia. This report describes two patients with this distinct tumour type but with no evidence of the paraneoplastic syndrome.
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PATIENT 1
A 55-year-old woman presented with a 3-month history of an asymptomatic, slowly enlarging mass in the left preauricular area. Past medical history was notable for bipolar disorder treated with lithium, and osteopenia, both stable for the past 15 years. The patient had not experienced any bony pain or fractures, and physical examination was unremarkable except for a firm, fixed 2 cm nodule in the left preauricular area. Ultrasound showed a poorly demarcated lesion blending into surrounding tissues, positron emission tomography CT was indeterminate, and MRI showed homogeneous enhancement on T1 and T2 weighted images. Open incisional biopsy was performed, followed by superficial parotidectomy.
PATIENT 2
A 53-year-old man presented with a 4-month history of a protuberant and painful mass in the left anterior pretibial region in December 2005. In 1995, and again in 1998, the patient had undergone excisions of similar masses in the same location. Metabolic laboratory studies were within normal limits at the time of the initial excision and at the time of the recurrences. A review of systems revealed no evidence of bone pain or fractures. Radiological examination, consisting of a MRI of the left leg, a bone scan of the bilateral lower extremities (popliteal fossa and distal) and a chest x ray, demonstrated that the lesion did not involve the underlying bone and no fractures or evidence of osteomalacia were identified. An excisional biopsy of the mass was performed.
PATHOLOGICAL FINDINGS
Gross pathological examination revealed the masses to be circumscribed, multilobated, tan-yellow, firm, gritty and unencapsulated. Adjacent nodular areas of haemorrhage were present. Light microscopy demonstrated relatively well-circumscribed lesions, and satellite lesions were identified in regions adjacent to the largest mass in patient 2. Large portions of calcified matrix with a flocculent or grungy pattern were evident at low-power in both specimens (fig 1A). Bland-appearing spindle cells with normochromic, small nuclei and indistinct nucleoli admixed within a thin-walled capillary network comprised the majority of the masses (fig 1B). Portions of the spindle cell proliferation were mitotically active with a maximum of three mitotic figures per high power field. Numerous osteoclast-like giant cells and regions of woven bone were also identified (fig 1C and D). There was infiltration of the surrounding tissues despite the low-power appearance of circumscription. The diagnosis of phosphaturic mesenchymal tumour-mixed connective tissue variant (PMTMCT) was rendered in both cases.
DISCUSSION
It has been known since the early 1970s that most cases of oncogenic osteomalacia (OO), a paraneoplastic syndrome of renal phosphate wasting with resultant hypophosphataemia and osteomalacia, are associated with bone or soft-tissue neoplasms. While this important observation was first documented by Evans and Azzopardi,1 and seconded shortly thereafter by Olefsky et al2 PMTMCT as a distinct tumour subtype associated with this syndrome was much more recently substantiated in the landmark paper by Folpe et al.3 Included in the study by Folpe et al were three tumours with all the histological characteristics of PMTMCT, but where clinical evidence of OO could not be confirmed.
In such cases, it is important to meticulously examine the histology, ensuring that the specimens truly represent PMTMCT and not another tumour entity such as tenosynovial giant cell tumour, osteosarcoma, giant cell tumour of soft parts, or others. The bland, low-grade nuclei with rare mitoses found in PMTMCT can help distinguish it from osteosarcoma, which typically demonstrates high-grade, pleomorphic nuclei. Osteoid produced by osteosarcoma is often dense and pink, curvilinear, with arborisation and abortive lacunae, in contrast to the grungy, flocculent matrix produced in PMTMCT. Tenosynovial giant cell tumours often arise in the hand, and contain variable numbers of multinucleated giant cells amid a background of mononuclear histiocytoid cells, which may be round to spindle-shaped. Nuclear features of these histiocytoid cells again may help in the diagnosis, as they are often grooved, and may be reniform. Also, areas of true ossification are not characteristic of tenosynovial giant cell tumour, but are frequently found in PMTMCT. Giant cell tumour of soft parts can display areas of ossification, typically as a “shell” of woven bone near the periphery of the mass, but the primary cell type, in addition to the multinucleated giant cells, is a round to ovoid mononuclear cell as opposed to the spindle cells seen in PMTMCT. Also, the stroma of giant cell tumour of soft parts is prominently vascular, lacking the calcification and overall grungy appearance of the stroma of PMTMCT.
It could be argued that histological criteria alone may be neither sufficiently sensitive nor specific for diagnosis of PMTMCT, and there are several case reports proposing additional studies that may aid in distinguishing PMTMCT from other histologically similar tumours. Toyosawa, et al, reported dentin matrix protein 1 expression as a unique feature of this tumour, particularly a perinuclear staining pattern.6 Also, PMTMCT has been shown to contain lymphatics, in contrast to other soft-tissue neoplasms with which it may be confused,7 suggesting that this could be another useful diagnostic aid.
The biochemical basis of OO has been attributed to tumour cells’ overexpression of fibroblast growth factor 23 (FGF-23), which, when overproduced, leads to marked decrease in bone mineralisation in animal models.4 FGF-23 is also known to be mutated in autosomal dominant hypophosphataemic rickets.5 As with any substance, there may be a spectrum of production of FGF-23 by PMTMCT cells. This spectrum would include PMTMCT producing such minute amounts of FGF-23 as to be clinically silent, or producing a deformed, inactive variant of the protein. This hypothesis has been proposed by other noted bone and soft-tissue pathologists1 but, unfortunately, no appropriate tissue was available to study FGF-23 production from either of the patients in this case report.
We present two patients with tumours of prototypical PMTMCT histology but with no clinical or laboratory evidence of OO, further demonstrating this tumour can occur independent of the paraneoplastic syndrome. Subsequent investigation of FGF-23 expression by such “clinically silent” PMTMCT will be necessary to test the hypothesis that such tumours express low levels of FGF-23, or a variant, chemically inactive, protein.
Take-home message
Phosphaturic mesenchymal tumour-mixed connective tissue variant is a rare tumour classically associated with oncogenic osteomalacia. It is important to remember that the occurrence of the neoplasm can be independent of the clinical syndrome.
Footnotes
Competing interests: None.
Patient consent: Obtained.