Phosphaturic Mesenchymal Tumors

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1		Guido Zavatta	--	1122	2023-08-17 21:09:47	\|
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This entry is adapted from the peer-reviewed paper 10.3390/curroncol30080541

Phosphaturic mesenchymal tumors (PMT) are rare neoplasms, which can give rise to a multifaceted syndrome, otherwise called tumor-induced osteomalacia (TIO). Localizing these tumors is crucial to obtain a cure for the phosphate metabolism derangement, which is often the main cause leading the patient to seek medical help, because of invalidating physical and neuromuscular symptoms.

phosphaturic tumor tumor-induced osteomalacia phosphatonin Fgf-23 TIO Osteomalacia Phosphate metabolism

1. Introduction

Phosphaturic mesenchymal tumors (PMT) are rare neoplasms, which can give rise to a multifaceted syndrome, otherwise called tumor-induced osteomalacia (TIO). TIO is extremely rare and epidemiology on this condition is currently unknown. Approximately 450 PMTs have thus far been reported in the literature ^[1]. The skeleton is affected in its whole by the biological consequences of small proteic substances secreted by PMTs, which usually localize within the bone or in the soft tissue. The peptides secreted by these tumors, called phosphatonins, cause the kidneys to lose more phosphate than usual, thus leading to demineralization of the skeleton, fractures or pseudofractures ^[2]. FGF-23 is the best known phosphatonin to date. Localizing these tumors is crucial to obtain a cure for the phosphate metabolism derangement, which is often the main reason for the patient to seek medical help, because of invalidating physical and neuromuscular symptoms. Of note, phosphate is a mainly intracellular anion, which serves as a key mediator in many physiological processes.

To make things even more complicated, a proportion of these tumors is completely silent and may grow unnoticed, unless they become large enough to produce pain or discomfort. FGF-23 can be produced by several benign or malignant lesions. In fact, TIO can be caused by tumors other than PMTs, such as odontogenic fibroma, hemangiopericytomas, giant cell tumor of tendons and, in a minority of cases, phosphaturic malignant tumors. Although the histology of these tumors is usually benign ^[3], local aggressiveness must be considered, possibly causing multiple recurrences after first resection.

The phosphate metabolism, radiology and histology of these rare tumors must be assessed by a multidisciplinary team aimed at curing the disease locally, as well as improving patients’ quality of life.

2. Imaging and Radiological Features of PMTs

Most cases of TIO are caused by PMTs, and are usually due to excess FGF-23. Locations are odd, making them often difficult to detect by radiologists. PMTs are found in the bone or soft tissues ^[4]. Lower extremities and head and neck are the two commonest sites ^[5]. Roughly half of cases (53%) occur in the bone, the other remaining cases in the soft tissue (45%) and in the skin (2%) ^[6]^[7].

Nuclear medicine imaging has been suggested to be the most accurate method to locate these tumors. For example, technetium bone scintigraphy, Gallium-68 DOTATATE and DOTANOC PET can be used as first-line functional tools to locate the tumors in a whole body scan ^[8]; one of these studies suggested also that Ga-DOTATATE PET/CT had a greater sensitivity and specificity, useful for the localization of PMTs in TIO ^[9], which can be a difficult diagnostic point due to variety of presentation and localization of this heterogeneous pathology.

In the field of oncology, Whole-Body MRI (WB-MRI) is also increasingly being used for the detection of metastatic bone tumors or lymph nodes metastasis in more centers. Coronal STIR sequences along with T1w sequences are useful in finding areas of bone edema secondary to fracture, while the use of DWI (Diffusion-Weighted Imaging) is still controversial and to be further investigated for this group of tumors ^[10]. It would be useful to conduct an investigation to evaluate the value of DWI in PMT diagnosis and characterization, as well as to examine the relationship between DWI findings and histological characteristics, particularly in distinguishing benign from malignant PMTs.

While the majority of the published literature on imaging studies of PMTs is focused on the choice of the best modality in localizing the tumors, little literature is available on the imaging features of PMTs masses.

For a better characterization of the lesion, after localization, CT scan can be easily performed. If the tumor is localized in soft tissues, on CT scans, the tumor exhibits a round or oval, well-bordered, isodense/hypodense soft tissue mass and displays a uniform enhancement when the tumor is small ^[4]; instead, bone lesions appear as typical osteolytic areas, show a narrow zone of transition and commonly contain internal matrix ^[1]. The disadvantage of CT lies in the use of ionizing radiation.

MRI plays an important role in lesion characterization and does not involve ionizing radiation. Considering the different histopathological variants of the tumor, the variant affecting mixed connective tissue (PMT-MCT), can present a typical MR appearance. On T1-weighted imaging, the tumor can be isointense compared to muscle, while on T2-weighted imaging the tumor is usually hyperintense. Consistent homogenous enhancement on post contrast T1w fat-suppression imaging is usually seen. However, it is necessary to consider that size can alter the signal and characteristic of the lesion. On the one hand, small PMTs might display homogeneous signal intensity both on T1w and T2w and uniform enhancement after T1wI contrast. By contrast, large tumors may show more heterogeneity on T2w, T1w, as well as on post-contrast T1w images. Heterogeneous low signals derive from vascular flow voids ^[4], or from matrix ^[11]. Differential diagnosis should be made with any soft tissue mass, including neurofibroma, hemangioma, leiomyoma, giant cell tumor, hemangioendothelioma, fibroma, neurofibrosarcoma. When PMTs are within the bone, any focal bone lesion such as solitary fibrous tumors, fibrous dysplasia or giant cell tumors should be considered in the differential diagnosis ^[1]. As such, clinical presentation and laboratory correlation are critical to PMT recognition and accurate diagnosis.

Regarding functional imaging, octreotide-based radiotracers appear to show the greatest advantages in detecting PMTs in comparison with other commonly used radiotracers such as 18F-fluorodeoxyglucose (¹⁸F-FDG). This is because PMTs express the somatostatin receptor (SSTR). ⁶⁸Ga DOTATATE demonstrates high affinity for somatostatin receptor 2 (SSTR2), which is highly expressed in these tumors. ⁶⁸Ga DOTATATE positron emission tomography (PET) combined with computed tomography has been suggested to be a better radioisotope than ¹⁸F-FDG-CT, because some PMTs do not take up ¹⁸F-FDG. ⁶⁸Ga-DOTATATE PET/CT demonstrated may be the best single study for localization of PMTs in TIO. Importantly, the imaging procedure must be performed from head to toe, to also include body extremities. This should be specifically demanded from the technician acquiring the images ^[8]^[9].

It would be useful to conduct a large prospective and multicenter investigation to establish which imaging approach is the most sensitive and specific for early identification and exact localization, by comparing different imaging modalities.

For now, the clinician should consider the advantages of integrating different imaging techniques, such as PET/CT, MRI, and CT to localize PMTs accurately. Multicenter studies with centralized imaging could be performed to define the best imaging technique/s in TIO.

References

Folpe, A.L. Phosphaturic mesenchymal tumors: A review and update. Semin. Diagn. Pathol. 2019, 36, 260–268.
Salassa, R.M.; Jowsey, J.; Arnaud, C.D. Hypophosphatemic Osteomalacia Associated with Nonendocrine Tumors. N. Engl. J. Med. 1970, 283, 65–70.
Ryan, E.A.; Reiss, E. Oncogenous osteomalacia: Review of the world literature of 42 cases and report of two new cases. Am. J. Med. 1984, 77, 501–512.
Shi, Z.; Deng, Y.; Li, X.; Li, Y.; Cao, D.; Coossa, V.S. CT and MR imaging features in phosphaturic mesenchymal tumor-mixed connective tissue: A case report. Oncol. Lett. 2018, 15, 4970–4978.
Peterson, N.R.; Summerlin, D.-J.; Cordes, S.R. Multiple phosphaturic mesenchymal tumors associated with oncogenic osteomalacia: Case report and review of the literature. Ear Nose Throat J. 2010, 89, E11–E15.
Hendry, D.S.; Wissman, R. Case 165: Oncogenic Osteomalacia. Radiology 2011, 258, 320–322.
Fatani, H.A.; Sunbuli, M.; Lai, S.Y.; Bell, D. Phosphaturic mesenchymal tumor: A report of 6 patients treated at a single institution and comparison with reported series. Ann. Diagn. Pathol. 2013, 17, 319–321.
Agrawal, K.; Bhadada, S.; Mittal, B.R.; Shukla, J.; Sood, A.; Bhattacharya, A.; Bhansali, A. Comparison of 18F-FDG and 68Ga DOTATATE PET/CT in Localization of Tumor Causing Oncogenic Osteomalacia. Clin. Nucl. Med. 2015, 40, e6–e10.
El-Maouche, D.; Sadowski, S.M.; Papadakis, G.Z.; Guthrie, L.; Cottle-Delisle, C.; Merkel, R.; Millo, C.; Chen, C.C.; Kebebew, E.; Collins, M.T. 68Ga-DOTATATE for Tumor Localization in Tumor-Induced Osteomalacia. J. Clin. Endocrinol. Metab. 2016, 101, 3575–3581.
Nakanishi, K.; Sakai, M.; Tanaka, H.; Tsuboi, H.; Hashimoto, J.; Hashimoto, N.; Tomiyama, N. Whole-body MR Imaging in Detecting Phosphaturic Mesenchymal Tumor (PMT) in Tumor-induced Hypophosphatemic Osteomalacia. Magn. Reson. Med. Sci. 2013, 12, 47–52.
Broski, S.M.; Folpe, A.L.; Wenger, D.E. Imaging features of phosphaturic mesenchymal tumors. Skelet. Radiol. 2018, 48, 119–127.

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Ludovica Lotrecchiano

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Guido Zavatta

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Update Date: 18 Aug 2023

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1. Introduction

2. Imaging and Radiological Features of PMTs

References