FGF23-Associated Tumor-Induced Osteomalacia in a Patient With Small Cell Carcinoma

Sauder, Adrienne; Wiernek, Szymon; Dai, Xumin; Pereira, Renata C.; Yudd, Michael; Patel, Charvi; Golden, Andrew; Ahmed, Sana; Choe, Jin; Chang, Victor; Sender, Slawomir; Cai, Donghong

doi:10.1177/1066896915617828

Cited by 27 publications

(19 citation statements)

References 17 publications

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“…PMTs are usually small, benign and characterised by low grade and mitotic index, requiring PET imaging to be detected [3]. However, it has also been linked with malignant haematological and solid tumours such as leukaemia [14], head and neck cancer [15], B cell non-Hodgkin's lymphoma [16], sarcoma [17], anaplastic thyroid carcinoma [18], small cell lung cancer [19], prostate cancer [20] and adenocarcinoma of the colon [21].…”

Section: Discussionmentioning

confidence: 99%

Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature

Savva

Adhikaree

Madhusudan

et al. 2019

J Diabetes Metab Disord

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Objectives Oncogenic osteomalacia is a rare paraneoplastic metabolic syndrome that is characterised by severe hypophosphataemia, hyperphosphaturia and osteomalacia secondary to renal loss of phosphate. It is commonly caused by overproduction of fibroblast growth factor-23 (FGF23) from benign tumours of mesenchymal origin. Currently, there is no clear evidence on the management of oncogenic osteomalacia in patients with metastatic solid tumours. Methods We report a case of breast cancer-induced oncogenic osteomalacia and discuss its diagnosis and management. Results A 71-year-old woman with advanced breast cancer developed symptomatic oncogenic osteomalacia with raised FGF23, severe hypophosphataemia and hypocalcaemia. The electrolytic disturbances were exacerbated after the administration of bisphosphonates in the context of her oncological treatment. Systemic chemotherapy and maintenance endocrine treatment along with phosphate and calcium supplementation reduced the activity of oncogenic osteomalacia and resolved the electrolytic imbalances. Conclusions To our knowledge, this is the first reported case of oncogenic osteomalacia in a patient with breast cancer. Oncogenic osteomalacia constitutes a diagnostic and therapeutic challenge. Pre-clinical and clinical evidence suggest that a possible underlying mechanism is the presence of molecular alterations in the FGF/FGFR signalling pathway leading to overexpression of FGF23. In metastatic setting, anticancer treatment can potentially lead to the normalisation of the electrolytic disturbances and reduction of the activity of oncogenic osteomalacia. The use of antiresorptive therapy in patients with bone metastases can potentially trigger FGF23 overexpression. Its use should be guided by the patients' risk of skeletal-related events and electrolytic disturbances as well as the degree of activity of oncogenic osteomalacia.

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Section: Discussionmentioning

confidence: 99%

Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature

Savva

Adhikaree

Madhusudan

et al. 2019

J Diabetes Metab Disord

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“…It is also worth underlining that while Fetuin-A showed a higher expression in primary hepatocytes compared to HepG2; no difference was evident for FGF23 expression between the two diverse types of cells. The lack of any difference between the primary hepatocytes and the HepG2 cells is an important finding, since it is known that tumoral liver cells can non-physiologically express many FGFs (FGF8, FGF17, FGF18) 36 , 37 . In any case, our results are confirmatory of previous studies, which have demonstrated that FGF23 is expressed also in the liver cells 23 .…”

Section: Discussionmentioning

confidence: 99%

FGF23 and Fetuin-A Interaction in the Liver and in the Circulation

Mattinzoli¹,

Ikehata²,

Tsugawa³

et al. 2018

Int. J. Biol. Sci.

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Recently it has been demonstrated that Fetuin-A, an anti-inflammatory protein synthesized by the liver, is produced also in bone by an FGF23-regulated pathway. FGF23 has been also demonstrated to induce inflammatory cytokine production in the liver. This study aimed to explore if FGF23 plays a role in the Fetuin-A production in the liver cells too and the possible relationships with FGF23 pro-inflammatory effects.FGF23 and Fetuin-A were studied in liver, kidney and in plasma with immunochemistry, immunoprecipitation, western blot, chromatin immunoprecipitation, duolink, ELISA, qrtPCR methodology.FGF23 is produced, but not secreted by the liver cells. In hepatocytes and circulation, FGF23 was present only strictly linked to Fetuin-A, while Fetuin-A was found also in unbounded form. No link was observed in the kidney. FGF23 up to 600 pg/ml stimulates, while, at higher concentrations, reduces Fetuin-A expression. Notably, overall the range of concentrations, FGF23 stimulates Fetuin-A promoter, TNFα and IL6 expression. In the nucleus, FGF23 seems to act as a direct transcription factor of Fetuin-A promoter.These results suggest that FGF23 played a direct regulatory role in Fetuin-A expression in liver cells with a biphasic effect: Fetuin-A progressively increases when FGF23 increases up to 400-600 pg/mL, and declines at higher FGF23 concentrations. These results lead us to hypothesize: a) a possible epigenetic post-transcriptional regulation; b) a possible counter-regulatory effect of FGF23 induced inflammatory cytokines (TNFα/ NF-κB mechanism). This study could add an additional key for the interpretation of the possible mechanisms linking FGF23, Fetuin-A and inflammation in CKD patients and suggests a role for FGF23 as transcription factor.

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“…Distant lung metastasis has also been reported to be witnessed with a histologically benign PMT [ 53 , 54 ]. PMTs can present as paraneoplastic syndrome of carcinoma as well, relative reports involving ovarian cancer [ 55 ], prostate cancer [ 56 ], colon cancer [ 57 ] and lung cancer [ 58 ].…”

Section: Clinical Description and Evaluationmentioning

confidence: 99%

Tumor-induced osteomalacia

Yin

et al. 2018

Osteoporosis and Sarcopenia

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Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome characterized by hypophosphatemia resulting from decreased tubular phosphate reabsorption, with a low or inappropriately normal level of active vitamin D. The culprit tumors of TIO could produce fibroblast growth factor 23 which plays a role in regulating renal Pi handling and 25-hydroxyvitamin D 1α-hydroxylase activity. Chronic hypophosphatemia could eventually lead to inadequate bone mineralization, presenting as osteomalacia. The diagnosis should be considered when patients manifest as hypophosphatemia and osteomalacia, or rickets and needs to be differentiated from other disorders of phosphate metabolism, such as the inhereditary diseases like X-linked hypophosphataemic rickets, autosomal dominant hypophosphataemic rickets, autosomal recessive hypophosphataemic rickets and acquired diseases like vitamin D deficiency. Localization of responsible tumors could be rather difficult since the vast majority are very small and could be everywhere in the body. A combination of thorough physical examination, laboratory tests and imaging techniques should be applied and sometimes a venous sampling may come into handy. The technology of somatostatin-receptor functional scintigraphy markedly facilitates the localization of TIO tumor. Patients undergoing complete removal of the causative neoplasm generally have favorable prognoses while a few have been reported to suffer from recurrence and metastasis. For those undetectable or unresectable cases, phosphate supplements and active vitamin D should be administrated and curative intended radiotherapy or ablation is optional.

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FGF23-Associated Tumor-Induced Osteomalacia in a Patient With Small Cell Carcinoma

Cited by 27 publications

References 17 publications

Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature

Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature

FGF23 and Fetuin-A Interaction in the Liver and in the Circulation

Tumor-induced osteomalacia

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