Tarandeep Kaur MD, Eric T Rush MD, FAAP, FACMG, Rajib K Bhattacharya MD FACE. Running head: Phophaturic Mesenchymal Tumor Presenting as TIO

Transcription

1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report ACCR PHOSPHATURIC MESENCHYMAL HEEL TUMOR PRESENTING WITH TUMOR INDUCED OSTEOMALACIA Tarandeep Kaur MD, Eric T Rush MD, FAAP, FACMG, Rajib K Bhattacharya MD FACE From: Division of Endocrinology, Genetics, and Metabolism, University of Kansas Medical Center, KS Running head: Phophaturic Mesenchymal Tumor Presenting as TIO Corresponding address: Rajib K Bhattacharya MD FACE University of Kansas Medical Center 3901 rainbow Wesco 4024 Endocrinology and Metabolism Kansas City Kansas bhattara2@gmail.com

2 Objective: To help clinicians identify and treat patients with tumor-induced osteomalacia (TIO) resulting from a phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT) Methods: Describe the history, presentation, laboratory findings, diagnostic studies, treatment and literature review. Results: A 58-year-old female with no significant past medical history, presents with ongoing multiple bone pain for years. She had a bone scan showing multiple focal areas of increased uptake involving bilateral ribs, distal right tibia and left femoral neck, representing previously healed fractures. Her bilateral lower extremity MRI showed stress fractures of the anteromedial cortex right tibia and the left femoral neck. Phosphorus was noted to be 1.9 ( mg/dl) and alkaline phosphatase was 179 ( U/L). TmP/GFR was 0.438, which is low. An outside physician initiated patient on teriparatide, which showed BMD improvement after one year and then the teriparatide was stopped. Later she developed a nontraumatic pubic ramus fracture; teriparatide was resumed. While on teriparatide, she developed several new rib fractures. Due to declining phosphorus levels, further investigation led to an elevated FGF23 level of 243 RU/ml (<50). Tumor-Induced Osteomalacia (TIO) was strongly suspectedand a NMPET/CT Trunk Ga 68 DOTATATE showed a right heel soft tissue nodule. An FNA was performed confirming PMTMCT, positive for FGF23 mrna. After surgery, her symptoms resolved and her phosphorus normalized. Discussion: TIO is a rare paraneoplastic syndrome characterized by bone pain, muscle weakness, and fractures associated with persistent hypophosphatemia. Clinicians now have new imaging tools to help identify and treat patients with PMTMCT. Abbreviations: 1,25(OH)2D3 = 1,25-dihydroxyvitamin D3; 25-OH D = 25 OH vitamin D 3; CT = computed tomography; DOTATATE = 1,4,7,10 tetraazacyclododecane 1,4,7,10- tetraacetic acid tyrosine-3-octreotate; FDG = fluorodeoxyglucose; FGF23 = fibroblast growth factor 23; PTH = parathyroid hormone; PET = positron emission tomography; TIO = tumor-induced osteomalacia; PMTMCT = phosphaturic mesenchymal tumor,mixed connective tissue variant; MRI = magnetic resonance imaging; US = Ultrasound; FNA = Fine needle aspiration; BMD = Bone Mineral Density.

3 Introduction TIO is a rare paraneoplastic syndrome which manifests as renal phosphate wasting and resultant osteomalacia. Patients can also present with other musculoskeletal symptoms including pain, proximal muscle weakness, and fractures. Due to the general unawareness of this condition, there is usually a significant lag between the onset of symptoms and diagnosis. The delay from the onset of symptoms to diagnosis ranges from years (1). TIO s mean age of diagnosis is 40 to 45 years and there is an equal gender distribution. Robert McCance described the first case of TIO with weakness, gait disturbances, and low phosphate level whose symptoms completely resolved after resection of tumor found in the femur (2). The term phosphaturic mesenchymal tumor, mixed connective tissue type (PMTMCT) was introduced by Weidner and Santa Cruz to accurately describe the effect and origin of the tumor. PMTMCT was eventually added to the 2013 WHO classification of tumors of the soft tissue and bone (3). We present a case of a 58-year-old female with TIO resulting from PMTMCT of the heel which was undiagnosed for years. Case Report A 58-year-old female with no significant past medical history presented with undulating achiness in multiple joints for years. Her first manifestation was several years earlier, which was a stress fracture of the right foot that healed well. She had been treated by multiple providers, including chiropractic care, with no improvement in pain. Bone scan showed multiple focal areas of increased uptake, mainly involving the bilateral ribs, but increased uptake was also noted in the distal right tibia and the left femoral neck. Oncology evaluation was then performed with no evidence of malignancy. She continued to experience hip and leg pain; MRI of bilateral lower extremities was performed which showed stress fractures involving the anteromedial cortex of the right tibia and the inferior cortex of left femoral neck. CT chest was also performed and showed multiple rib fractures. The patient was referred to Endocrinology for evaluation of bone fragility. She had no history of falls, kidney stones, family history of osteoporosis or metabolic bone disease. She denied any smoking, alcohol, recreational drugs, and steroid use. Family history was significant only for breast cancer and hypertension. Her medications included calcium carbonate 500mg twice daily and vitamin D 1000 IU daily.

4 The physical examination was unremarkable with normal dentition and no skeletal deformities. She had a previous history of elevated alkaline phosphate and bone scans, X- Rays or CT scans did not show any evidence of Paget s disease. Other laboratory testing showed normal calcium, urinary calcium, thyroid and 24-hour urinary cortisol levels. DXA was performed, showing L1-L4 T-score of -0.7 and left femoral neck T-score. Due to ongoing fractures without any etiology, she was started on teriparatide by an outside provider and was continued until seen in our clinic. While on teriparatide, she had laboratory evaluation significant for a phosphorus of 1.9 ( mg/dL), alkaline phosphatase of 179 ( U/L), and bone-specific alkaline phosphatase of 51 mcg/l (<22). Prior to teriparatide treatment, her phosphorus level was 2.2 mg/dl, and PTH was normal, with normal 25-OH vitamin D levels as summarized in the table. TmP/GFR was calculated at 0.438, which was felt to be inappropriately low. Repeat DXA bone density one year later showed an L1-L4 T-score of -0.3 and femoral neck T-score of The teriparatide was then stopped due to a significant increase in bone mineral density. Eight months after stopping teriparatide, she presented with increased rib and hip pain and X-rays showed possible right pubic ramus fracture. Teriparatide was then restarted. The reemergence of rib pain prompted CT of the chest which revealed multiple rib fractures, including. nonunion of a right fifth rib fracture. A repeat DXA after one year showed a 5.4% decrease in femoral neck BMD.. The patient was taken off teriparatide and phosphorus remained low at 1.5 mg/dl, with a normal 25-OH vitamin D level. A persistently low serum phosphate with high serum alkaline phosphatase and raised concern for possible hypophosphatemic osteomalacia. Further testing to investigate this diagnosis led to the discovery of an elevated FGF23 of 243 RU/ml (<50). The test was performed in Mayo clinic labs. The kit uses 2 affinity-purified goat antibodies that bind at the carboxy terminal portion of fibroblast growth factor 23 (FGF23). One antibody is coated onto microtiter wells and the other is biotinylated. Horseradish peroxide conjugated to avidin and 3.3', 5,5'-tetramethylbenzidine (TMB) substrate provide the colored product, which is read in a microtiter plate spectrophotometer

5 On a thorough clinical examination, she was noted to have a nontender lump in her right heel. She underwent NMPET/CT Trunk Ga 68 DOTATATE which revealed a 1.6x 1.2cm soft tissue density nodule with central calcific density in a soft tissue of the right heel demonstrating moderately increased radiotracer activity. An US-guided FNA was performed of the mass which was consistent with PMTMCT, histologically benign, positive for FGF23 mrna expression. The patient underwent resection of the tumor in August 2017 and final pathology was consistent with PMTMCT forming a 1.5x 1.1cm circumscribed mass. The final pathology report reviewed frozen sections after Hematoxylin and Eosin staining. The final pathological report incorporated the FNA biopsy describing positive marker for FGF23 expression. Phosphorus and FGF23 levels postoperatively normalized. Six months after surgical resection of the tumor the patient had a phosphorus level of 4.4 mg/dl and a normal FDF 23 of 73. She described no new fractures. She experienced significant reduction in overall bone pain and described increased mobility. DXA performed one year postoperatively showed a 34% increase in bone density in the spine (L1-L4), with T-score of 2.7 and 31% increase in bone density in the right femoral neck, with T-score of At the time of drafting of this manuscript, she has been fracture free. Discussion The diagnosis of TIO was delayed in our patient for years as PMTMCTs tend to be small and, may not be easily detectable on physical exam or bone scans. Presentation with recurrent fractures and associated metabolic abnormalities such as hypophosphatemic raises suspicion for an underlying tumor. Reported cases of TIO to date reveals that 50 55% of the tumors have been reported to arise from soft tissues and 40 45% in bones (4). Thigh and femur tend to be the most common anatomical sites (22.7%), followed by the craniofacial region (20.7%), ankle and foot (8.8%), pelvis (8.2%), tibia and fibula (6.5%), and arms (6.5%) (4). Tumor cells produce FGF23, a physiologic regulator of phosphate levels. FGF23 decreases proximal tubule reabsorption of phosphate and inhibits 1-α-hydroxylase, which reduces levels of 1-α, 25 (OH) 2 D3. Thus, oversecretion of FGF23 by the tumor cells leads to increased excretion of phosphate in the urine, mobilization of calcium and phosphate from

6 bones, and the reduction of osteoblastic activity, ultimately resulting in widespread osteomalacia (5). Renal tubular phosphate wasting is confirmed by calculation of tubular reabsorption of phosphate (TRP) and/or tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR). When the blood phosphate is normal, TRP should be 85 95%; TRP and TmP/GFR are decreased in patients with TIO, thus leading to excess urinary phosphate loss. (6). FDG positron emission tomography, coupled with computed tomography (FDG-PET/CT), is thought to be the most sensitive method for detecting PMTMCT, but poor specificity limits the value of this modality (7). Recently, modified octreotide molecules ((Tyr3)-octreotate) have been combined with chelators as DOTATATE or DOTANOC and then conjugated with positron emitting isotopes like 68 Ga. This compound is utilized to generate PET scans such as 68 Ga-DOTATATE and combined with CT for anatomical correlation ( 68 Ga-DOTATATE PET/CT). 68 Ga-DOTATATE PET/CT demonstrates the greatest sensitivity and specificity, suggesting that it may be the best single study for localization of PMTMCTs (7). MRI is the most frequently utilized anatomical modality. The most typical radiographic appearance of PMTMCTs is a well-defined lytic lesion on computed tomography (CT) and a T2 hyperintense and enhancing lesion on MRI. If multiple suspicious lesions are found, selective venous sampling with FGF23 measurement has been shown to be a sensitive and specific technique for confirming a lesion. FGF23 concentration ratio (between the venous drainage of the tumor bed and the general circulation) > 1.6 is considered as the diagnostic cut-point; this technique has a sensitivity of 87% and a specificity of 71% (8). Resection of the tumor is the ultimate definitive treatment. A 10 mm margin for extremity lesions and 5 mm for trunk lesions is recommended (9). Since FGF23 has a short half-life of minutes a rapid resolution of symptoms upon surgical removal is expected. Surgical cure is evidenced by normalization of the serum biochemical abnormalities including serum phosphate level and usually seen within 5 days (9). Late recurrence happens in a small percentage of patients so long-term follow-up is warranted after the surgery. Metastasis most commonly occurs in the lung. For patients with inoperable tumors, radiofrequency ablation has been used. (10). Adjuvant radiotherapy has been recommended in cases of recurrence where repeat surgery would lead to significant disability or if there are positive margins after surgery. (9).

7 Medical therapy is recommended for patients who cannot undergo surgery. Phosphate supplementation, mg/kg per day of elemental phosphate divided into 4 6 doses (typically 1 3 g/day) is needed. Calcitriol can also be considered for therapy due to reduced levels of 1,25 OH Vitamin D. Other experimental therapies which are being studied include the humanized anti-fgf23 antibody which might be of therapeutic value for TIO in patients who cannot undergo surgery (11). Conclusion Clinicians who are faced with patients with recurrent fractures, generalized pain, and low serum phosphorus should consider the rare condition of tumor-induced osteomalacia. It is appropriate to obtain screening laboratory studies to assess for TIO and other causes of osteomalacia. Hypophosphatemia with elevated alkaline phosphorus level should prompt further diagnostic investigations including evaluation for a FGF23-producing tumor. Surgical resection of the tumor can lead to complete resolution of symptoms. References 1. Chong W.H., Molinolo A.A., Chen C.C., Collins M.T. Tumor-induced osteomalacia. Endocr. Relat. Cancer. 2011;18:R McCance RA. Osteomalacia with Looser's nodes (Milkman's syndrome) due to a raised resistance to vitamin D acquired about the age of 15 years. Q J Med. 1947; 16: Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets.weidner N, Santa Cruz D. Cancer Apr 15; 59: Beygi S, Denio A, Sharma TS. The Foot That Broke Both Hips: A Case Report and Literature Review of Tumor-Induced Osteomalacia. Case Reports in Rheumatology. 2017;2017: Ghorbani-Aghbolaghi A, Darrow MA, Wang T. Phosphaturic mesenchymal tumor (PMT): exceptionally rare disease, yet crucial not to miss. Autopsy & Case Reports. 2017;7:32-37.

8 6. Florenzano P, Gafni RI, Collins MT. Tumor-induced osteomalacia. Bone Reports. 2017;7: 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. 68 Ga-DOTATATE for tumor localization in tumor-induced osteomalacia. J. Clin. Endocrinol. Metab. 2016;101: Andreopoulou P., Dumitrescu C.E., Kelly M.H., Brillante B.A., Cutler Peck C.M., Wodajo F.M., Chang R., Collins M.T. Selective venous catheterization for the localization of phosphaturic mesenchymal tumors. J. Bone Miner. Res. 2011;26: Minisola S., Peacock M., Fukumoto S., Cipriani C., Pepe J., Tella H.T., Collins M.T. Tumorinduced osteomalacia. Nat Rev Dis Primers. 2017;13: Hesse E., Rosenthal H. & Bastian L 2007b Radiofrequency ablation of a tumor causing oncogenic osteomalacia. New England Journal of Medicine Aono Y., Hasegawa H., Yamazaki Y., Shimada T., Fujita T., Yamashita T & Fukumoto S Anti-FGF23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. Journal of Bone and Mineral Research Table 1. Laboratory Data Ref. Range Post Surgery Calcium mg/dl Creatinine mg/dl 0.73 Phosphorus mg/dl PTH pg/ml hour urine mg/ calcium hours 25(OH) vitamin D ng/ml Alkaline Phosphate U/L Bone-specific alkaline phosphate < 22 mcg/l 51 FGF- 23 < 50 RU/ml , 25 OH vitamin D pg/ml 52 TSH MCU/ml 0.895

9 Table 2 Bone Density Trends BMD T Score Percent Change from Previous AP Spine L1-L4 8/ % 5/ g/cm Right Femur 8/ g/cm % 5/ g/cm 2-1.0