Nonremission and Recurrent Tumor‐Induced Osteomalacia: A Retrospective Study

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ABSTRACT

Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome. It is curable by excision of the causative tumor. However, a few cases may persist or relapse after tumor resection. We aimed to investigate the rate of these events and related factors. We retrospectively studied TIO patients treated with surgery in a tertiary hospital. TIO was established based on a pathologic examination or the reversion of hypophosphatemia. Refractory TIO patients consisted of those with nonremission or recurrent hypophosphatemia after surgery. A total of 230 patients were confirmed as having TIO. After primary surgery, 26 (11.3%) cases persisted, and 16 (7.0%) cases recurred. The overall refractory rate was 18.3%. The median time of recurrence was 33 months. Compared with patients in the recovery group, patients in the refractory group were more likely to be female (59.5% versus 41.0%, p = .029) and have a lower serum phosphate level (0.44 ± 0.13 versus 0.50 ± 0.11 mmol/L, p = .002). The refractory rate was lowest in head/neck tumors (7.5%) and highest in spine tumors (77.8%). Regarding the tissue involved of tumor location, the refractory rate was higher in tumors involving bone than tumors involving soft tissue (32.7% versus 7.0%, p < .001). The outcomes of malignant tumors were worse than those of benign tumors ( p < .001): nonremission rate, 21.4% versus 9.7%; recurrence rate, 28.6% versus 6.5%. In the multivariate regression analysis, female sex, spine tumors, bone tissue‐involved tumors, malignancy, and low preoperation serum phosphorus levels were identified as risk factors for refractory outcomes. High preoperative fibroblast growth factor 23 (FGF23) levels were also associated with refractory after adjusting for involving tissue and tumor malignancy. In summary, we are the first to report the rate and clinical characteristics of refractory TIO in a large cohort. For patients with multiple risk factors, especially spine tumors, clinical practitioners should be aware of a poor surgical prognosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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Most cited references 19

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Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Markku Miettinen, Richard J. Zaino, Michael J. Econs … (2003)

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive "grungy" calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

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Tumour-induced osteomalacia

Salvatore Minisola, Munro Peacock, Seijii Fukumoto … (2017)

Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.

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Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature.

Li Jing, Man-Mei Li, T C B F Silva … (2012)

Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult-onset hypophosphatemic osteomalacia were seen over a 6-year period (January, 2004 to May, 2010) in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium-99m octreotide scintigraphy ((99) Tc(m) -OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in (99) Tc(m) -OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by (99) Tc(m) -OCT. The gender distribution was equal (M/F = 19/20). Average age was 42 ± 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 ± 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult-onset hypophosphatemia in China. (99) Tc(m) -OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long-term follow-up. Copyright © 2012 American Society for Bone and Mineral Research.

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Author and article information

Contributors

Weibo Xia:

ORCID: https://orcid.org/0000-0001-7768-5536

xiaweibo8301@163.com

Journal

Journal ID (nlm-ta): J Bone Miner Res

Journal ID (iso-abbrev): J. Bone Miner. Res

Journal ID (doi): 10.1002/(ISSN)1523-4681

Journal ID (publisher-id): JBMR

Title: Journal of Bone and Mineral Research

Publisher: John Wiley & Sons, Inc. (Hoboken, USA )

ISSN (Print): 0884-0431

ISSN (Electronic): 1523-4681

Publication date (Electronic): 15 November 2019

Publication date (Print): March 2020

Volume: 35

Issue: 3 ( doiID: 10.1002/jbmr.v35.3 )

Pages: 469-477

Affiliations

[ ¹ ] Department of Endocrinology, Key Laboratory of Endocrinology, NHC Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China

[ ² ] Department of Nuclear Medicine Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China

[ ³ ] Department of Pathology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China

[ ⁴ ] Department of Orthopedic Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China

[ ⁵ ] Department of Radiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China

[ ⁶ ] Department of Ear, Nose, and Throat (ENT) Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China

[ ⁷ ] Department of Stomatology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China

[ ⁸ ] Department of Ultrasound Diagnosis Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China

Author notes

[*] [* ]Address all Address correspondence to: and requests for reprints to: Weibo Xia, MD, Department of Endocrinology, Key Laboratory of Endocrinology, NHC, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing Street, Dongcheng District, Beijing 100730, China. E‐mail: xiaweibo8301@ 123456163.com

Author information

Xiang Li https://orcid.org/0000-0003-1625-5748

Mei Li https://orcid.org/0000-0001-7270-4902

Xiaoping Xing https://orcid.org/0000-0002-2759-5177

Weibo Xia https://orcid.org/0000-0001-7768-5536

Article

Publisher ID: JBMR3903

DOI: 10.1002/jbmr.3903

PMC ID: 7140180

PubMed ID: 31643101

SO-VID: a633ef5e-25af-47c9-8d07-f52713beb4e0

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This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 16 August 2019

Date revision received : 14 October 2019

Date accepted : 17 October 2019

Page count

Figures: 4, Tables: 3, Pages: 9, Words: 7051

Funding

Funded by: CAMS Innovation Fund for Medical Science

Award ID: 2016‐I2M‐3‐ 003

Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;

Award ID: 81170805

Award ID: 81670714

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cover-date March 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.9 mode:remove_FC converted:08.04.2020

ScienceOpen disciplines: Human biology

Keywords: prognosis,recurrent,refractory,surgery,tumor‐induced osteomalacia

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ScienceOpen disciplines: Human biology

Keywords: prognosis, recurrent, refractory, surgery, tumor‐induced osteomalacia

Nonremission and Recurrent Tumor‐Induced Osteomalacia: A Retrospective Study

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Most cited references 19

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Tumour-induced osteomalacia

Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature.

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