FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review

Abstract

Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.

SINCE 1960, several articles have reported patients with malignant neoplasms, including small cell lung cancer and prostate adenocarcinoma, who developed chronic hypophosphatemia [1-25]. A certain type of phosphate wasting syndrome (i.e., Fanconi syndrome) has been suggested as an underlying mechanism in these patients, but the precise etiology for this condition remains to be elucidated. In 2000, fibroblast growth factor (FGF) 23 was identified as the causative gene for autosomal dominant hypophosphatemic rickets [26], and FGF23 protein was cloned from the tumor sample of a patient with tumor-induced osteomalacia (TIO) in 2001 [27]. Afterward, the measurement of FGF23 in patients with small cell lung cancer or prostate cancer who developed chronic hypophosphatemia revealed that chronic hypophosphatemia in these patients was mediated by the oversecretion of FGF23 [9, 20-24]. We also introduced two cases where FGF23-related hypophosphatemia was unintentionally identified in patients with small cell lung cancer and prostate small cell carcinoma in the course of a clinical study to evaluate the clinical performance of the FGF23 assay [28]. Furthermore, we recently conducted retrospective questionnaire surveys regarding TIO among physicians from the Japanese Society for Bone and Mineral Research and the Japan Endocrine Society and revealed that five cases without identified causative tumors in the bone and soft tissue from all 88 TIO-suspected patients (6%) had concomitant advanced malignant tumors [25]. These five patients had lung adenocarcinoma (n = 2), prostate cancer (n = 2), and gastric cancer (n = 1), which raised the suspicion that FGF23 was ectopically secreted from these malignant tumors [25]. However, reports with a detailed description of the time course of the biochemical data, including serum intact FGF23 and phosphate levels along with histological analysis, are scarce. We described a patient with small cell lung cancer presenting chronic hypophosphatemia, which was clinically diagnosed as FGF23-related hypophosphatemia, along with a syndrome of inappropriate antidiuretic hormone secretion (SIADH) and adrenocorticotropic hormone (ACTH)-dependent hypercortisolemia. The time course of the biochemical data, including FGF23 and serum phosphate, and histology were also evaluated. We also review previous published cases of renal wasting hypophosphatemia in patients with malignancy, discussing the potential pathogenetic mechanism underlying this rare paraneoplastic syndrome.

Case Report

A 52-year-old female with stage IV small cell lung cancer and metastatic lesions in the liver, bone, brain, and pancreas was referred to our department for the evaluation of chronic hypophosphatemia and concomitant pathologic fracture in the cervical spine (Fig. 1). At the initial visit, she was medicated with esomeprazole, magnesium oxide, calcium carbonate, cholecalciferol, magnesium carbonate, rupatadine, pregabalin, oxycodone, senna, and naldemedine. She did not drink alcohol and was never administered an iron preparation infusion.

Fig. 1

Chest computed tomography (CT) scan and ¹⁸F-FDG PET/CT (FDG-PET) before referral to our department

(A) Chest CT shows the primary lesion at the left hilum of the lung (white arrowhead).

(B) FDG-PET shows multiple metastases in the spine (yellow arrowheads) and liver (red arrowheads).

One month before the referral to our division, the patient was admitted to the respiratory department for chemotherapy, and laboratory data first revealed severe hypophosphatemia and mild hypocalcemia, although her phosphate and calcium levels had been within the normal range one year prior. Two weeks after the recognition of hypophosphatemia and hypocalcemia, she also developed hyponatremia and hypercortisolemia.

She was then referred to our department for further evaluation of the abovementioned abnormalities of serum phosphate and calcium. The maximal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) and tubular reabsorption of phosphate (%TRP) were severely reduced to 0.58 mg/dL and 57.9%, respectively, suggesting that renal phosphate wasting was the etiology of her hypophosphatemia. As she had previously been treated with cisplatin, Fanconi syndrome due to cisplatin was initially suspected, although she did not present hypouricemia or glucosuria. For the differential diagnosis of chronic hypophosphatemia, intact FGF23 levels were measured and revealed an inappropriately unsuppressed level of 48.4 pg/mL (reference range under chronic hypophosphatemia, <30 pg/mL, Minaris Medical, Tokyo, Japan), suggesting FGF23-related hypophosphatemia (Table 1A) [28-30]. Furthermore, laboratory data also showed ACTH-dependent hypercortisolemia and hyponatremia (Table 1A). Regarding ACTH-dependent hypercortisolemia, the 1 mg dexamethasone suppression test (DST) and 8 mg DST were performed and revealed an absence of suppression of ACTH and cortisol (ACTH 587.9 pg/mL, cortisol 85.2 μg/dL [1 mg DST]; ACTH 616.9 pg/mL, cortisol 86.0 μg/dL [8 mg DST]). Next, both the corticotropin-releasing hormone stimulation test and the desmopressin stimulation test failed to induce a significant elevation of ACTH levels. Pituitary tumors were not detected by enhanced pituitary magnetic resonance imaging. Considering that the patient had small cell lung cancer, ectopic ACTH syndrome was clinically suspected. Additionally, hyponatremia due to SIADH was diagnosed because the suppression of plasma ADH levels under hyponatremia was insufficient. Other related data, including urinary sodium excretion, urine osmolarity, normal kidney function, and sufficient cortisol levels, were compatible with the diagnosis of SIADH, which is also associated with small cell lung cancer (Table 1A). Next, the formalin-fixed paraffin-embedded specimen of small cell lung cancer obtained by biopsy a year prior was subjected to immunohistochemistry, revealing negative expression for FGF23 and ACTH (Fig. 2). Water restriction and increased salt intake did not fully improve her hyponatremia; therefore, tolvaptan was initiated and normalized her hyponatremia (Table 1A).

Table 1

Time course of biochemical profiles and results of the octreotide loading test in a patient with small cell lung cancer

(A) Time course of biochemical profiles

	Reference range, adult	At the initiation of chemotherapy	Referral to our division	Two months after referrala
eGFR (mL/min/1.73 m2)	>60	91.0	141.0	98.5
Sodium (mmol/L)	138–145	137	119	145
Potassium (mmol/L)	3.6–4.8	4.1	4.2	3.6
Phosphorus (mg/dL)	2.7–4.6	4.1	1.1	2.6
Albumin corrected calcium (mg/dL)	8.8–10.1	9.0	7.9	9.1
%TRP	81–90	—	57.9	78.8
TmP/GFR (mg/dL)	2.3–4.3	—	0.58	2.0
Urinary calcium (g/gCre)	0.04–0.28	—	0.09	0.21
Urinary sodium (meq/L)	—	—	104	111
Urine osmolality (mOsm/kgH2O)	50–1,200	—	574	495
ALP (U/L)	38–113	74	147	244
1,25(OH)2D (pg/mL)	20–60	—	144	54
25(OH)D (ng/mL)	—	—	19.0	—
i-PTH (pg/mL)	26–76	—	154	—
FGF23 (pg/mL)	0–29.9	—	48.4	83.7
ADH (pg/mL)	0–2.8	—	1.5	2.5
ACTH (pg/mL)	8.7–61.5	—	311.2	1,537.7
Cortisol (μg/dL)	4.4–21.1	9.7	39.8	44.4
NSE (ng/mL)	<16.3	29.7	73.9	—
Pro-GRP (pg/mL)	<80.9	242.7	776.7	—

(B) Results of the octreotide loading test

	0 hr	2 hr	4 hr	6 hr	8 hr	12 hr	24 hr
FGF23 (pg/mL)	36	34	38	36	40	32	39
ACTH (pg/mL)	555.2	582.2	571.6	578.7	520.8	559.4	580.2
Cortisol (μg/dL)	59.4	66.4	63.6	68.3	67.6	66.0	73.9

eGFR, estimated glomerular filtration rate; TRP, tubular reabsorption of phosphate; ALP, alkaline phosphatase; 1,25(OH)₂D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; i-PTH, intact parathyroid hormone; FGF, fibroblast growth factor; ADH, antidiuretic hormone; ACTH, adrenocorticotropic hormone; NSE, neuron-specific enolase; Pro-GRP, pro-gastrin-releasing peptide

All blood samples and urine samples were collected in the fasting state in the morning.

^a Two months after the initiation of phosphate supplementation, metyrapone, and tolvaptan

Fig. 2

Histological findings of small cell lung cancer before developing FGF23-related hypophosphatemia

(A) Hematoxylin and eosin stain; (B) FGF23; (C) ACTH.

Scale bars are 100 μm.

Subsequently, an octreotide loading test was performed to evaluate the suppressive effect of octreotide on ACTH and FGF23, but there was no significant suppression of either hormone (Table 1B). Therefore, we decided to initiate metyrapone for ACTH-dependent hypercortisolemia and inorganic phosphate supplementation and activated vitamin D for FGF23-related hypophosphatemia, and the final doses of metyrapone, alfacalcidol, and inorganic phosphate were 3,000 mg, 2 μg, and 800 mg, respectively, at the last visit in the observed period. After the initiation of treatment, serum phosphate levels immediately improved (Fig. 3). On the other hand, the serum cortisol level could not be adequately controlled even with the maximum dose (3,000 mg/day) of metyrapone. Sulfamethoxazole-trimethoprim and spironolactone were also initiated to prevent the comorbidities associated with hypercortisolemia, such as infection and hypokalemia. Anti-resorptive drugs were not administered for fracture prevention because these drugs might increase the risk of pseudofracture and fracture in cases with FGF23-related hypophosphatemia. Although the patient was treated with chemotherapy for two months, the tumor burden increased, and the serum level of FGF23 doubled with a stable phosphate level and kidney function (Fig. 3).

Fig. 3

Temporal profiles of serum FGF23 and phosphate levels

Square and circle plots indicate serum FGF23 and phosphate levels, respectively. Arrows indicate the timing of chemotherapy. The red area is the reference value of the serum phosphate level, and the blue area is the reference value of the serum FGF23 level under chronic hypophosphatemia.

Discussion

In the present case report, a patient with stage IV small cell lung cancer presumably developed oversecretion of ADH, ACTH, and intact FGF23, which were clinically diagnosed as SIADH, ACTH-dependent hypercortisolemia, and FGF23-related hypophosphatemia. Additionally, the time course of serum phosphate and FGF23 levels was followed for two months to explore the response to supplementary phosphate, active vitamin D, and chemotherapy for small cell lung cancer after the diagnosis of FGF23-related hypophosphatemia. To our knowledge, this case report is the first to diagnose FGF23-related hypophosphatemia by measuring serum intact FGF23 levels and to follow the clinical course in detail in a patient with small cell lung cancer.

To date, several case reports have introduced patients with small cell lung carcinoma who developed hypophosphatemia. Table 2 is the literature review of malignancy patients suspected of renal wasting hypophosphatemia. Among the total of 52 patients, prostate cancer was the most common (26 patients [50%]), followed by lung cancer (11 patients [21%]). Since the measurement of FGF23 was not available until 2002 [44], the majority of these case reports did not include the value of serum FGF23 and only provided the values of serum phosphate levels, TRP and TmP/GFR, which could not differentiate the causes for acquired forms of chronic hypophosphatemic osteomalacia (i.e., Fanconi syndrome, vitamin D deficient osteomalacia, and FGF23-related hypophosphatemic osteomalacia). Several case reports presented elevated C-terminal FGF23 levels in patients with small cell lung cancer, prostate cancer, blood cancer, colon cancer, breast cancer, pancreas tumor, ovarian cancer, brain tumor, and thyroid cancer [9, 20, 23, 31-35, 37, 38] (Table 2). However, C-terminal FGF23 measures inactive C-terminal FGF23 fragments in addition to active intact FGF23, where C-terminal FGF23 fragments could be increased under some specific clinical conditions, including chronic inflammation and iron deficiency [45-48]. Therefore, measurement of intact FGF23 should be required for the precise diagnosis of FGF23-related hypophosphatemia. Two cases with lung adenocarcinoma or lung cancer of undetermined histology measured intact FGF23 at one point [25], and only nine case reports with other types of cancer measured intact FGF23 [21, 22, 24, 25, 39, 40, 42, 43] (Table 2).

Table 2

Literature review of cases with malignancy who were suspected of renal wasting hypophosphatemia

No	Age/Sex	Histology	Metastasis	Serum P (mg/dL)	c-FGF23 (RU/mL)	i-FGF23 (pg/mL)	Urinary P excretion	Ectopic hormone	Ref
(A) Lung cancer
1	57/M	Small cell	Liver, spine	1.2–1.7	NE	NE	1,000 mg (24 hr urine)	ADH	[1]
2	37/M	Small cell	Spine	1.5	NE	NE	0.83 mg/dL (TmP/GFR)	ACTH, ADH	[2]
3	59/M	Small cell	Spine, rib	0.7	NE	NE	<0.3 mg/dL (TmP/GFR)	ADH	[3]
4	58/M	Small cell	Liver, pancreas, adrenal glands, vertebrae	1.1	NE	NE	54% (%TRP)	ACTH	[4]
5	72/M	Small cell	None	0.8	NE	NE	64% (%TRP)	ADH	[5]
6	46/M	Small cell	Bone marrow	1.2–1.9	NE	NE	1.4 mg/dL (TmP/GFR)	ACTH, ADH	[6]
7	60/M	Small cell	Liver	1.2	NE	NE	41% (FePO4)	ADH	[7]
8	74/F	Small cell	Liver, adrenal gland	2.1	NE	NE	NE	ACTH, calcitonin	[8]
9	60/M	Small cell	Liver	0.7	575	NE	1,895 mg (24 hr urine)	None	[9]
10	61/F	Adenocarcinoma	None	1.3	NE	3,900	NE	None	[25]
11	94/M	Undetermined	None	1.9	NE	61	NE	None	[25]
(B) Prostate cancer
12	64/M	Not described	Bone	2.2	NE	NE	65% (%TRP)	None	[10]
13	66/M	Not described	Lung, liver, bone	1.4	NE	NE	1.4 mg/dL (TmP/GFR)	None	[11]
14	61/M	Not described	Yes	1.43	NE	NE	0.87 mg/dL (TmP/GFR)	None	[12]
15	74/M	Not described	Yes	1.68	NE	NE	1.22 mg/dL (TmP/GFR)	None	[12]
16–21	NA	Not described	Bone	1.6 2.9 2.7 2.0 2.1 2.6	NE	NE	NE	None	[13]
22	70/M	Not described	Pelvis, spine, scapula	1.8	NE	NE	NE	None	[14]
23–26	NA	Not described	None	2.0 ± 0.7	NE	NE	1.2 ± 0.2 mg/dL (TmP/GFR)	None	[15]
27	88/M	Adenocarcinoma	Spine, pelvis, ribs	1.9	NE	NE	1.8 mg/dL (TmP/GFR)	None	[16]
28	65/M	Adenocarcinoma	Lung, liver, diaphragm, bone	1.7	NE	NE	0.6 mg/dL (TmP/GFR)	None	[17]
29	69/M	Not described	Bone	0.5	NE	NE	High	None	[18]
30	66/M	Adenocarcinoma	Bone	1.6	NE	NE	1.18 mg/dL (TmP/GFR)	None	[19]
31	83/M	Adenocarcinoma	Bone	1.4	326	NE	1.25 mg/dL (TmP/GFR)	None	[20]
32	71/M	Adenocarcinoma	Bone	0.6	NE	36.4	0.40 mg/dL (TmP/GFR)	ACTH	[21]
33	63/M	Adenocarcinoma	Bone	2.1	NE	176	54% (FePO4)	None	[22]
34	84/M	Adenocarcinoma	Bone	<0.3	454.8	NE	62% (%TRP)	None	[23]
35	53/M	Adenocarcinoma	Bone	1.1	NE	1,890	NE	None	[24]
36	59/M	Not described	Bone	0.8	NE	369	NE	None	[25]
37	71/M	Not determined	Bone	0.6	NE	471	NE	None	[25]
(C) Blood cancer
38	72/F	CLL	None	1.5	161	NE	NE	None	[31]
39	68/F	B-NHL	None	0.7	154	NE	56% (%TRP)	None	[32]
40	22/M	Acute leukemia	None	1.0	9,650	NE	1,101 mg (24 hr Urine)	None	[33]
41	33/F	NK-T cell lymphoma	None	1.5	1,940	NE	43% (FePO4)	None	[34]
(D) Gastric cancer
42	62/F	Not described	None	1.7	NE	81	NE	None	[25]
(E) Colon cancer
43	80/F	Adenocarcinoma	Liver	0.4	674	NE	34% (FePO4)	None	[35]
(F) Renal cancer
44	18/M	Clear cell	None	1.3	NE	NE	NE	None	[36]
(G) Breast cancer
45	71/F	Not described	Bone	<1.0	311	NE	NE	None	[37]
46	47/F	Duct carcinoma	Liver, sternum, spine, ilium	<0.9	2,430	NE	56% (FePO4)	None	[38]
47	55/M	Duct carcinoma	Liver, lung, acetabulum, ilium	1.4	548	NE	78% (FePO4)	None	[38]
(H) Pancreas tumor
48	77/F	NE	None	2.3	765	491.1	0.9 mg/dL (TmP/GFR)	None	[39]
(I) Ovarian cancer
49	57/F	Undifferentiated carcinoma	Thyroid, lung, liver, spine	1.6	NE	501.6	75% (%TRP)	None	[40]
50	11/F	Granulosa cell	None	2.6	NE	NE	0.85 mg/dL (TmP/GFR)	PTHrP	[41]
(J) Brain tumor
51	60/F	NE	None	2.2	NE	132	28% (FePO4)	None	[42]
(K) Thyroid cancer
52	59/F	Anaplastic carcinoma	Lungs, mediastinum, liver, left greater trochanter	0.9	NE	2,355	1,169 mg (24 hr urine)	None	[43]

M, male; F, female; NA, not available; CLL, Chronic lymphocytic lymphoma; B-NHL, B-cell non Hodgkin lymphoma; NK, natural killer; NE, not examined; P, phosphate; c-FGF23, C-terminal fibroblast growth factor 23; i-FGF23, intact fibroblast growth factor 23; TmP, tubular maximum reabsorption rate of phosphate; GFR, glomerular filtration rate; TRP, Tubular Reabsorption of Phosphate; FePO₄, fractional excretion of phosphate; ACTH, adrenocorticotropic horomone; ADH, antidiuretic hormone; PTHrP, parathyroid hormone-related peptide

The current case presented biochemical profiles of intact FGF23 and serum phosphate levels, which supported the concrete diagnosis of FGF23-related hypophosphatemia. In addition, we followed the intact FGF23 levels for two months and observed a doubling of FGF23 levels along with the increase in ACTH and ADH levels and tumor size. Although histological evaluation after developing FGF23-related hypophosphatemia was not available, the increase in ACTH and ADH levels, which are positively correlated with the increase in tumor size, suggested that these two hormones are at least possibly produced from the lung cancer.

The genetic background on how small cell lung cancers obtain ectopic hormonal production is still uncertain. No study has revealed the genetic background of ACTH and ADH secretion from small-cell lung cancer. In contrast, one case report evaluates the molecular mechanism regarding FGF23 production [9]. In this study, the expression of FGF1, FGFR1, WNT3a, CTNNB1, and FGF23 was evaluated by reverse transcription-polymerase chain reaction, and CTNNB1 and WNT3a were highly expressed, while the expressions of FGF1 and FGFR1, a phosphate sensor on osteocytes regulating the serum FGF23 concentration [49], were similar to that of nontumor areas. With regard to endocrine tumors, gain-of-function mutations in CTNNB1, which encodes β-catenin, were found to be nonspecific driver mutations for cortisol-producing adenoma and aldosterone-producing adenoma, suggesting that β-catenin signaling might be involved in the production and secretion of different hormones [50]. Accordingly, gain-of-function mutation of CTNNB1 or other genes in the Wnt/β-catenin signaling pathway may be an explainable and causal single driver mutation for multiple ectopic hormonal secretions, including FGF23 in this case, as already suggested in a previous case report [9].

Because hypophosphatemic osteomalacia leads patients to bone pain, pseudofractures, fractures, and muscle weakness, which severely deteriorate their quality of life, chronic hypophosphatemia needs to be corrected even in malignant cases. In contrast, anti-bone resorptive drugs such as bisphosphonate and denosumab might aggravate the risk of pseudofractures and fractures if these drugs are used to decrease skeletal-related events in malignant cases with bone metastasis and FGF23-related hypophosphatemia. Currently, the treatment for FGF23-related hypophosphatemia consists of conventional therapy, such as inorganic phosphate and activated vitamin D, and burosumab, an anti-FGF23 antagonizing monoclonal antibody. Our case successfully partially responded to conventional phosphate supplementation and active vitamin D, while serum phosphate levels remained low despite frequent repletion of sodium phosphate in another case with FGF23-related hypophosphatemia by colon cancer [35]. Response to phosphate supplementation might depend on the serum intact FGF23 levels; therefore, further studies are warranted to elucidate the appropriate treatment strategy and clinical characteristics of FGF23-related hypophosphatemia in patients with advanced malignant tumors. In conclusion, serum phosphate levels should be carefully monitored in patients with advanced malignant tumors, especially small cell lung cancer and castration-resistant prostate cancer, to detect FGF23-related hypophosphatemia in the early stage to prevent the progression of osteomalacia and avoid the use of anti-bone resorptive drugs. Data from future studies are anticipated to reveal the molecular and genetic mechanism on FGF23-related hypophosphatemia in patients with advanced malignant tumors.

Author’s Contributions

Kato H, Tamiya H, Kawakami M, Kage H, and Ito N conceptualized the article. Kato H, Kimura S, Taguchi M, Sunouchi T, Koga M, Manaka K, Tamiya H, Kawakami M, Kage H, and Ito N analyzed and interpreted the data. Kato H drafted the body of the manuscript. Ito N critically reviewed the publication. All authors contributed to the article and approve the submitted version.

Informed Consent

Informed consent was obtained from the patient for publication of this case report.

Funding Source

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure

None of the authors have any potential conflicts of interest associated with this research.

References

• 1   Taylor  HC,  Fallon  MD,  Velasco  ME (1984) Oncogenic osteomalacia and inappropriate antidiuretic hormone secretion due to oat-cell carcinoma. Ann Intern Med 101: 786–788.
• 2   Banks  J,  Penney  MD,  Anderson  EG (1987) Tumour induced hypophosphataemia associated with small cell carcinoma of the bronchus. Thorax 42: 909–910.
• 3   Sinha  AK,  Deluise  M,  Pierce  R (1994) Tumour induced hypophosphataemia associated with small cell carcinoma of the lung. Aust N Z J Med 24: 322–323.
• 4   van Heyningen  C,  Green  ART,  MacFarlane  IA,  Burrow  CT (1994) Oncogenic hypophosphataemia and ectopic corticotrophin secretion due to oat cell carcinoma of the trachea. J Clin Pathol 47: 80–82.
• 5   Robin  N,  Gill  G,  van Heyningen  C,  Fraser  W (1994) A small cell bronchogenic carcinoma associated with tumoral hypophosphataemia and inappropriate antidiuresis. Postgrad Med J 70: 746–748.
• 6   Shaker  JL,  Brickner  RC,  Divgi  AB,  Raff  H,  Findling  JW (1995) Case report: renal phosphate wasting, syndrome of inappropriate antidiuretic hormone, and ectopic corticotropin production in small cell carcinoma. Am J Med Sci 310: 38–41.
• 7   Tantisattamo  E,  Ng  RCK (2011) Dual paraneoplastic syndromes: small cell lung carcinoma-related oncogenic osteomalacia, and syndrome of inappropriate antidiuretic hormone secretion: report of a case and review of the literature. Hawaii Med J 70: 139–143.
• 8   Coners  K,  Woods  SE,  Webb  M (2011) Dual paraneoplastic syndromes in a patient with small cell lung cancer: a case report. J Med Case Rep 5: 318.
• 9   Sauder  A,  Wiernek  S,  Dai  X,  Pereira  R,  Yudd  M, et al. (2016) FGF23-associated tumor-induced osteomalacia in a patient with small cell carcinoma: a case report and regulatory mechanism study. Int J Surg Pathol 24: 116–120.
• 10   Randall  RE,  Lirenman  DS (1964) Hypocalcemia and hypophosphatemia accompanying osteoblastic metastases. J Clin Endocrinol Metab 24: 1331–1333.
• 11   Hosking  DJ,  Chamberlain  MJ,  Shortland Webb  WR (1975) Osteomalacia and carcinoma of prostate with major redistribution of skeletal calcium. Br J Radiol 48: 451–456.
• 12   Lyles  KW,  Berry  WR,  Haussler  M,  Harrelson  JM,  Drezner  MK (1980) Hypophosphatemic osteomalacia: association with prostatic carcinoma. Ann Intern Med 93: 275–278.
• 13   Charhon  SA,  Chapuy  MC,  Delvin  EE,  Valentin-Opran  A,  Edouard  CM, et al. (1983) Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma with special reference to osteomalacia. Cancer 51: 918–924.
• 14   Kabadi  UM (1983) Osteomalacia associated with prostatic cancer and osteoblastic metastases. Urology 21: 65–67.
• 15   Murphy  R,  Wright  G,  Rai  GS (1985) Hypophosphataemic osteomalacia associated with prostatic carcinoma. Br Med J (Clin Res Ed) 290: 1945.
• 16   McMurtry  CT,  Godschalk  M,  Malluche  HH,  Geng  Z,  Adler  RA (1993) Oncogenic osteomalacia associated with metastatic prostate carcinoma: case report and review of the literature. J Am Geriatr Soc 41: 983–985.
• 17   Nakahama  H,  Nakanishi  T,  Uno  H,  Takaoka  T,  Taji  N, et al. (1995) Prostate cancer-induced oncogenic hypophosphatemic osteomalacia. Urol Int 55: 38–40.
• 18   Reese  DM,  Rosen  PJ (1997) Oncogenic osteomalacia associated with prostate cancer. J Urol 158: 887.
• 19   Pelger  RCM,  Lycklama À Nijeholt  GAB,  Papapoulos  SE,  Hamdy  NAT (2005) Severe hypophosphatemic osteomalacia in hormone-refractory prostate cancer metastatic to the skeleton: natural history and pitfalls in management. Bone 36: 1–5.
• 20   Cotant  CL,  Rao  PS (2007) Elevated fibroblast growth factor 23 in a patient with metastatic prostate cancer and hypophosphatemia. Am J Kid Dis 50: 1033–1036.
• 21   Ramon  I,  Kleynen  P,  Valsamis  J,  Body  JJ,  Karmali  R (2011) Hypophosphatemia related to paraneoplastic Cushing syndrome in prostate cancer: cure after bilateral adrenalectomy. Calcif Tissue Int 89: 442–445.
• 22   Mak  MP,  da Costa e Silva  VT,  Martin  RM,  Lerario  AM,  Yu  L, et al. (2012) Advanced prostate cancer as a cause of oncogenic osteomalacia: an underdiagnosed condition. Support Care Cancer 20: 2195–2197.
• 23   Latifyan  SB,  Vanhaeverbeek  M,  Klastersky  J (2014) Tumour-associated osteomalacia and hypoglycaemia in a patient with prostate cancer: is Klotho involved? BMJ Case Rep 2014: bcr2014206590.
• 24   Nishida  S,  Shigesawa  I,  Nagai  S,  Itoh  N,  Masumori  N (2021) [A Case of Prostate Cancer with Multiple Bone Metastasis with High FGF23 Value Indicated by Intractable Hypocalcemia and Hypophosphatemia]. Hinyokika Kiyo 67: 47–51 (In Japanese).
• 25   Hidaka  N,  Koga  M,  Kimura  S,  Hoshino  Y,  Kato  H, et al. (2022) Clinical challenges in diagnosis, tumor localization and treatment of tumor‐induced osteomalacia: outcome of a retrospective surveillance. J Bone Miner Res 37: 1479–1488.
• 26   White  KE,  Evans  WE,  O’Riordan  JLH,  Speer  MC,  Econs  MJ, et al. (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26: 345–348.
• 27   Shimada  T,  Mizutani  S,  Muto  T,  Yoneya  T,  Hino  R, et al. (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 98: 6500–6505.
• 28   Ito  N,  Kubota  T,  Kitanaka  S,  Fujiwara  I,  Adachi  M, et al. (2021) Clinical performance of a novel chemiluminescent enzyme immunoassay for FGF23. J Bone Miner Metab 39: 1066–1075.
• 29   Fukumoto  S,  Ozono  K,  Michigami  T,  Minagawa  M,  Okazaki  R, et al. (2015) Pathogenesis and diagnostic criteria for rickets and osteomalacia—proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society. J Bone Miner Metab 33: 467–473.
• 30   Kato  H,  Hidaka  N,  Koga  M,  Ogawa  N,  Takahashi  S, et al. (2022) Performance evaluation of the new chemiluminescent intact FGF23 assay relative to the existing assay system. J Bone Miner Metab 40: 101–108.
• 31   Stewart  I,  Roddie  C,  Gill  A,  Clarkson  A,  Mirams  M, et al. (2006) Elevated serum FGF23 concentrations in plasma cell dyscrasias. Bone 39: 369–376.
• 32   Elderman  JH,  Wabbijn  M,  de Jongh  F (2016) Hypophosphataemia due to FGF-23 producing B cell non-Hodgkin’s lymphoma. BMJ Case Rep 2016: bcr2015213954.
• 33   Reinert  RB,  Bixby  D,  Koenig  RJ (2018) Fibroblast growth factor 23-induced hypophosphatemia in acute leukemia. J Endocr Soc 2: 437–443.
• 34   Zheng  G,  Kanduri  SR,  Canterbury  JP,  Nguyen  T,  Velez  JCQ (2021) A case of hypophosphatemia due to oncogenic osteomalacia in a patient with natural killer T-cell lymphoma. Kidney Blood Press Res 46: 647–651.
• 35   Leaf  DE,  Pereira  RC,  Bazari  H,  Jüppner  H (2013) Oncogenic osteomalacia due to FGF23-expressing colon adenocarcinoma. J Clin Endocrinol Metab 98: 887–891.
• 36   Jin  X,  Jing  H,  Li  F,  Zhuang  H (2013) Osteomalacia-inducing renal clear cell carcinoma uncovered by 99mTc-Hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) scintigraphy. Clin Nucl Med 38: 922–924.
• 37   Savva  C,  Adhikaree  J,  Madhusudan  S,  Chokkalingam  K (2019) Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature. J Diabetes Metab Disord 18: 267–272.
• 38   Abramson  M,  Glezerman  IG,  Srinivasan  M,  Ross  R,  Flombaum  C, et al. (2021) Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer. Clin Nephrol 95: 104–111.
• 39   Pickering  ME,  Bouvier  D,  Puravet  A,  Soubrier  M,  Sapin  V, et al. (2022) Hypophosphatemia related to a neuro-endocrine tumor of the pancreas: A case report. Clin Biochem 104: 62–65.
• 40   Lin  HA,  Shih  SR,  Tseng  YT,  Chen  CH,  Chiu  WY, et al. (2014) Ovarian cancer-related hypophosphatemic osteomalacia—a case report. J Clin Endocrinol Metab 99: 4403–4407.
• 41   Ubetagoyena Arrieta  M,  Martinez Sainz de Jubera  J,  García de Andoin Barandiaran  N,  Úriz Monaut  JJ,  López Cuesta  S, et al. (2017) Hypercalcemia and hypophosphatemia in a 11 years old girl with ovarian tumor. Nefrologia 37: 100–101.
• 42   Tarasova  VD,  Trepp-Carrasco  AG,  Thompson  R,  Recker  RR,  Chong  WH, et al. (2013) Successful treatment of tumor-induced osteomalacia due to an intracranial tumor by fractionated stereotactic radiotherapy. J Clin Endocrinol Metab 98: 4267–4272.
• 43   Abate  EG,  Bernet  V,  Cortese  C,  Garner  HW (2016) Tumor induced osteomalacia secondary to anaplastic thyroid carcinoma: a case report and review of the literature. Bone Rep 5: 81–85.
• 44   Yamazaki  Y,  Okazaki  R,  Shibata  M,  Hasegawa  Y,  Satoh  K, et al. (2002) Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 87: 4957–4960.
• 45   Imel  EA,  Peacock  M,  Gray  AK,  Padgett  LR,  Hui  SL, et al. (2011) Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab 96: 3541–3549.
• 46   Farrow  EG,  Yu  X,  Summers  LJ,  Davis  SI,  Fleet  JC, et al. (2011) Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A 108: E1146–E1155.
• 47   Ito  N,  Wijenayaka  AR,  Prideaux  M,  Kogawa  M,  Ormsby  RT, et al. (2015) Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Mol Cell Endocrinol 399: 208–218.
• 48   David  V,  Martin  A,  Isakova  T,  Spaulding  C,  Qi  L, et al. (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89: 135–146.
• 49   Takashi  Y,  Kosako  H,  Sawatsubashi  S,  Kinoshita  Y,  Ito  N, et al. (2019) Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation. Proc Natl Acad Sci U S A 166: 11418–11427.
• 50   Zennaro  MC,  Boulkroun  S,  Fernandes-Rosa  F (2017) Genetic causes of functional adrenocortical adenomas. Endocr Rev 38: 516–537.