Prostate Cancer-Induced Oncogenic Hypophosphatemic Osteomalacia

Nakahama, Hajime; Nakanishi, Teruyuki; Uno, Hiromi; Takaoka, T; N, Taji; Uyama, Osamu; Kitada, O; Sugita, Michio; Miyauchi, Akimitsu; Sugishita, Tadashi

doi:10.1159/000282746

Cited by 38 publications

(7 citation statements)

References 3 publications

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“…These findings strongly suggest that the neoplasm produced a phosphatonin other than FGF23. [3][4][5][6] There is also a recent report of a patient with TIO secondary to disseminated colonic adenocarcinoma, in which the colonic carcinoma was FGF23 immunoreactive using a more recently developed antibody. 10,[34][35][36] It is also notable that the ovarian serous carcinoma, from a patient with disseminated disease, elevated serum FGF23 levels, and clinical TIO, was negative for FGF23 mRNA expression by CISH.…”

Section: Discussionmentioning

confidence: 99%

A Novel Chromogenic In Situ Hybridization Assay for FGF23 mRNA in Phosphaturic Mesenchymal Tumors

Carter

Caron

Doğan

et al. 2015

American Journal of Surgical Pathology

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Phosphaturic mesenchymal tumors of the mixed connective tissue type (PMT) are very rare tumors of bone and soft tissues. Most patients with PMT have long-standing osteomalacia secondary to production of fibroblast growth factor 23 (FGF23), a hormone that inhibits phosphate reuptake within the renal proximal tubule. Previously, we have reported the detection of FGF23 mRNA in PMT by reverse transcription polymerase chain reaction (PCR); however, the low specificity and risk for nontumoral tissue contamination inherent in PCR-based methodology limit its clinical utility. We evaluated RNAscope as a semiquantitative method of in situ FGF23 mRNA detection in the diagnosis of PMT. Twenty-five PMTs (median 52 y, range 5 to 73 y) occurred in patients with tumor-induced osteomalacia (TIO), manifesting as masses (mean 3.9 cm, range 1.4 to 12 cm) in various bones and soft tissues. FGF23 mRNA was positive in 96% (22/23) informative cases of PMT: 16 cases scored 3+; 5 scored as 2+; 1 scored as 1+. Among these cases, FGF23 mRNA was detected in 3 malignant PMTs along with their metastases. Forty control cases included aneurysmal bone cyst (N=4), chondromyxoid fibroma (N=8), high-grade osteosarcomas (N=8), and (nonfamilial) tumoral calcinosis, as well as miscellaneous cartilage-forming tumors or osteoid-forming tumors and soft tissue tumors. All control cases were negative for FGF23 mRNA in the lesional cells. One aneurysmal bone cyst had rare FGF23 mRNA-expressing osteocytes clustered around remodeled bone. One ovarian serous carcinoma in a patient with disseminated disease, elevated serum FGF23, and TIO was negative for FGF23 mRNA in the neoplastic cells. We conclude that RNAscope is a highly sensitive and specific, semiquantitative in situ hybridization method of FGF23 mRNA detection applicable to formalin-fixed, paraffin-embedded tissues. Detection of FGF23 expression is a valuable diagnostic adjunct, especially in patients with occult TIO. Compared with reverse transcription PCR, this method preserves tissue morphology and reduces "false positives" related to detection of endogenous FGF23 mRNA expression by osteocytes.

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Section: Discussionmentioning

confidence: 99%

A Novel Chromogenic In Situ Hybridization Assay for FGF23 mRNA in Phosphaturic Mesenchymal Tumors

Carter

Caron

Doğan

et al. 2015

American Journal of Surgical Pathology

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“…Most cases of TIO are related to mesenchymal neoplasms, while TIO secondary to epithelial neoplasms is rarely reported, particularly in cases of prostate carcinoma [2]. Although different kinds of mesenchymal neoplasms were thought to cause TIO, Folpe et al (2004) revealed that histologically uniform neoplasms known as phosphaturic mesenchymal tumors (PMTs) are the main cause of TIO associated with mesenchymal neoplasms [3,4].…”

Section: Introductionmentioning

confidence: 99%

ERG and FLI1 are useful immunohistochemical markers in phosphaturic mesenchymal tumors

et al. 2015

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Phosphaturic mesenchymal tumors (PMT) are the most common cause of tumor-induced osteomalacia (TIO) related to mesenchymal neoplasms. The lineage of differentiation of PMTs has not been elucidated in existing literature. Fourteen cases of PMT were analyzed for this study to elucidate its lineage. We used vascular and/or lymphatic endothelial markers for the immunohistochemical analysis, which included CD31, CD34, factor VIII-related antigen, podoplanin, Freund's leukemia integration site 1 (FLI1), and avian v-ets erythroblastosis virus E26 oncogene homolog (ERG). FLI1 and ERG were stained in all cases with proportion of immunopositive tumor cells largely more than 50 %; staining intensity was moderate or strong for both FLI1 and ERG. The tumor cells were stained with CD31 and/or CD34, with significantly less staining than observed for FLI1 and ERG. The tumor cells were completely immunonegative for factor VIII-related antigen and podoplanin. FLI1 and ERG are known to have considerable specificity to endothelial cells; ERG is more widely equipped in surgical pathology laboratories than FLI1. We concluded that ERG (or FLI1 if available) is useful marker for the diagnosis of PMT, and that PMTs may have an endothelial cell lineage.

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“…2-4,6-10,12,14-16,18-22,24-26,28-34,37,38,41-46,49-57,59-69, 71-79,82-90,92-107,109,110 The overwhelming majority of cases of OO are associated with soft tissue or bone neoplasms, although a small number of cases of OO have been reported in association with syndromes such as neurofibromatosis-1 38 and McCune-Albright syndrome, 46,108 and in patients with carcinomas. 17,53,55 It has been shown that OO-associated mesenchymal tumors overexpress fibroblast growth factor-23 (FGF-23), a recently described protein capable of inhibiting renal tubular epithelial phosphate transport, 1 and this is now thought to be the mechanism underlying most cases of OO. 91 Although the overwhelming majority of OO-associated mesenchymal tumors have been reported as simply "garden variety" soft tissue and bone tumors of various types (eg, hemangiopericytoma, hemangioma, giant cell tumor, osteoblastoma), it has been recognized by certain investigators that many of these tumors are, in fact, quite distinctive, when carefully evaluated.…”

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confidence: 99%

Most Osteomalacia-associated Mesenchymal Tumors Are a Single Histopathologic Entity

Folpe

Fanburg‐Smith²,

Billings

et al. 2004

The American Journal of Surgical Pathology

587

547

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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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Prostate Cancer-Induced Oncogenic Hypophosphatemic Osteomalacia

Cited by 38 publications

References 3 publications

A Novel Chromogenic In Situ Hybridization Assay for FGF23 mRNA in Phosphaturic Mesenchymal Tumors

A Novel Chromogenic In Situ Hybridization Assay for FGF23 mRNA in Phosphaturic Mesenchymal Tumors

ERG and FLI1 are useful immunohistochemical markers in phosphaturic mesenchymal tumors

Most Osteomalacia-associated Mesenchymal Tumors Are a Single Histopathologic Entity

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