PTH like substance secreting mesenchymal tumor causing oncogenic osteomalacia; unravelling the difficulties in localization – A report of 2 cases

Abstract

Background

Oncogenic osteomalacia is a rare paraneoplastic association of Phosphaturic mesenchymal tumor (PMT) secreting excessive levels of a PTH like substance. They usually remain undiagnosed and patients suffer for years. The rarity of this tumor and its non-specific clinical presentations poses great challenge to the treating surgeons. Its management is poorly described in literature. We report two of such rare cases without much diagnostic delay.

Case report

We had 2 cases; A 53-year-old south east Asian male with 6 months of debilitating pain over multiple sites, and another 44-year-old male patient with complaints of low back ache, and pain over both lower and upper limbs for 1.5 years. Both had low serum phosphorus and elevated FGF-23 values, but all other parameters were normal. A PMT was suspected and confirmed on a Ga⁶⁸- DOTATOC scan in both cases, and on complete excision, their symptoms and the altered blood parameters got normalized. Histology was consistent with PMT.

Conclusion

Accurate and timely diagnosis of a PMT with non-specific features are extremely challenging, but not without solutions. Even though a tumor of rarity, with the appropriate imaging modalities like Ga⁶⁸- DOTATOC scan, and estimation of FGF-23 and serum phosphorus levels, they can be diagnosed. Once identified, complete removal is often curative within a few months.

1. Introduction

Tumor induced osteomalacia (TIO), also known as Oncogenic osteomalacia is a rare paraneoplastic manifestation, which causes excessive secretion of a PTH like substance from a tumor leading to hypophosphatemia and bone demineralization.¹ Oncogenic osteomalacia presents characteristically with prolonged musculoskeletal weakness and lower limb pain not responding adequately with analgesics. The multiple bone pains are due to fragility fractures resulting from impaired vitamin-D and phosphate metabolism

The increased secretion of PTH or related peptides shifts calcium and phosphates from bone matrix, which eventually decreases the osteoblastic activity and leads to phosphaturia. FGF-23 is a peptide hormone synthesized primarily from osteogenic cells and osteocytes. It serves as a major biological regulator of serum phosphate by modulating the parathyroid gland, kidney, and the metabolism of vitamin-D.² Also increased levels of PTH or PTH like substances leads to over expression of FGF-23.

Osteomalacia, the adult variant of rickets, when induced as a distant effect of a rare tumor, is very difficult to localize. The diagnosis of TIO is extremely challenging as the symptoms are often non-specific. It may include generalized myalgia, fatigue, bone pain, and non-responding muscle weakness. Moreover, the diagnosis is often delayed as a matter of rarity of this tumor and it being not so familiar to the clinicians.²

Even if the suspicion of a TIO is possible from the distinct laboratory values, the PMT (phosphaturic mesenchymal tumor) itself is non-traceable most of the times.^{3 68}Ga-DOTA PET-CT is the most accurate imaging technique for locating PMTs.⁴ Even after the localization and tissue studies, the relative unfamiliarity of the characteristic histology and the existence of several variants including hormonally inactive subsets of the PMT delays the diagnosis by clinical pathologists.⁵

At times, prolonged bone pains with hypophosphatemia, hyperphosphaturia and elevated FGF- 23 levels fetches the diagnosis. But it is more important to anatomically locate and excise the tumor as the complete removal dramatically normalizes the lab values and the disabling symptoms within 2–3 months.⁶

2. Case report

2.1. Case - 1

A 53year old south east Asian male was referred to our orthopaedic centre with history of pain over both legs, shoulders, bilateral chest, and lower back for 6 months and severe pain on right foot for 5 months duration. It was following an implant removal from his left leg, after which he experienced persistent dull pain, which went on worsening, making him unable to walk and he was home-bound thereafter. On examination, there was a swelling of firm to hard consistency about 3x2x0.5 cm over the dorsum of right midfoot with no fixity to underlying bone. There was no swelling elsewhere. There was no distal neuro vascular deficit.

On investigations, he had a low serum phosphorous level (1.70 mg/dL), and high serum fibroblast growth factor-23(FGF23)–485.51 RU/ml. Rest of the biochemical parameters including calcium and parathormone were normal. MRI suggested marrow edema with stress fractures in talus, calcaneum and lower tibia, and an ovoid area of 25x16×14mm abnormal signal intensity over dorsum of right 3rd metatarsal. There was no definitive evidence of malignant/metastatic lesion on Tc-MDP Bone scan (with SPECT CT). But there was an increased focal uptake in soft tissue density over dorsum right midfoot anterior to lateral cuneiform on Ga⁶⁸- DOTATOC scan. On suspicion of a PMT causing osteomalacia, we did a wide local excision of the lesion along with tenolysis and neurolysis of the extensor compartment of the foot. Histopathological study showed it as a well-defined soft tissue neoplasm with multiple foci of coarse calcification (smudgy calcification), with osseous metaplasia and some osteoclastic giant cells, which was consistent as that of a PMT. Few dilated vessels in the macroscopic appearance gave a hemangiopericytoma like appearance also. 2 weeks after the excision, patient had tremendous improvement in his symptoms and his blood parameters came to normal levels. Then, he gradually started weight bearing and has returned to work by the end of 2 months. 1 year down the line, he was completely free of his complaints. (see Fig. 1, Fig. 2, Fig. 3, Fig. 4)

Fig. 1.

Case No- 1; Xray of bilateral distal leg and ankle showing reduced bone density.

Fig. 2.

Case No- 1; ⁶⁸Ga DOTATOC image showing increased tracer uptake on the dorsum of right midfoot region.

Fig. 3.

Case No- 1; Intra-operative image depicting wide local excision of the lesion.

Fig. 4.

Case No- 1; Histological image depicting multiple foci of coarse calcification (smudgy calcification), with osseous metaplasia and some osteoclastic giant cells.

2.2. Case- 2

A 44-year-old man, without any comorbidities or traumatic event, came with complaints of low back ache, and pain over both lower and upper limbs for a duration of 1.5 years. He had an insidious onset of gradually progressive continuous dull aching pain, which worsened on lying down and on waking up from the bed. By the end of 1 year, he developed difficulty in walking and was using a walker to move around for the last 6 months of his illness. He did undergo multiple imaging studies at multiple centres before he showed up to our centre. On examination, there was a firm spherical swelling of 3x2x1cm over the medial aspect of right proximal thigh in the subcutaneous plane. The skin over the swelling was normal and there was no distal neurovascular deficit. He had a low serum phosphorus of 1.60mg/Dl, and a high FGF-23 of 352.4 RU/ml, and calcium, PTH and rest of the biochemical parameters were normal. Imaging studies of the dorso-lumbar spine showed hypointensity on multiple vertebrae with poor bone quality. Bone scan revealed an asymmetric active polyarthritis and bilateral sacroilitis. ⁶⁸Ga-DOTATOC PET/CT revealed somatostatin (SST) receptor expressing soft tissue density lesion (2.0 × 1.2 cm) in the subcutaneous plane in the proximal aspect of the right medial thigh which was consistent with MRI.

With the definitive diagnosis as TIO, he was planned for a wide local excision of the lesion. A circumferential incision was given with 1 cm tumor margin and it was excised in toto. Histopathological analysis revealed short fascicles of haphazardly arranged cells with oval to elongated deep stained nuclei, and ill-defined cytoplasmic margins with variably collagenized stroma and peripheral calcification. In addition, congested blood vessels and hemosiderin pigments seen but no evidence of atypia, mitotic activity or necrosis.

Postoperatively, the patient was on phosphorous supplements and other supportive medications. 2 months later he had drastic resolution of the symptoms and the blood parameters got normalized. By the end of 1 year follow up, he was quite comfortable, able to carry out his daily activities and ride a two-wheeler to his workplace (See Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9).

Fig. 5.

Case No- 2; Xray of dorso-lumbar spine showing decreased bone density and scalloping of vertebral bodies with kyphoscoliosis.

Fig. 6.

Case No- 2; ⁶⁸Ga DOTATOC images showing increased radio activity in the proximal aspect of the right medial thigh.

Fig. 7.

Case No- 2; Soft tissue lesion of 3x2x1cm, over the proximal aspect of the right medial thigh.

Fig. 8.

Case No- 2; Soft tissue lesion after wide local excision.

Fig. 9.

Case No- 2; Histopathology specimen showing bland sheet of spindle cells with small nuclei, hypocellularity, and hemangiopericytoma like vasculature.

3. Discussion

Phosphate is an important physiologic regulator of cellular metabolism and DNA synthesis. Acute hypophosphatemia manifests with non-specific features like hypotension, muscle weakness, congestive cardiac failure, rhabdomyolysis, pulmonary failure, and altered mentation which delays the diagnosis.⁷ Chronic hypophosphatemia causes bone demineralization resulting in bone pain due to stress fractures.

PATHOPHYSIOLOGY - The chief regulators of the phosphate metabolism are parathyroid hormone, calcitriol, and FGF-23. The important pathophysiological mechanisms involved in TIO are reduced intestinal absorption, intracellular trapping, and excessive renal loss of phosphate. In the renal tubules, PTH acts by lowering the proximal tubular reabsorption of phosphate and the active form of vitamin-D by inhibiting type 2a and 2c sodium-phosphate co-transporters (NaPi-2a2c), and the 1-alpha-hydroxylase enzyme respectively. Also, excessive levels of PTH and/or PTH like substances activates and increases the levels of FGF-23. FGF-23 is usually expressed in osteocytes and through its binding to klotho-FGF receptor complex, it regulates metabolism of vitamin-D and phosphate.⁸ So, when there is a tumor secreting a PTH like substance, there is an enhanced renal loss of phosphate, which results in hyperphosphaturia, hypophosphatemia, and low vitamin-D3 levels. Reduced levels of phosphate do interfere with the function of osteoblasts(collagen synthesis and mineralization) and hence, the effective formation of calcium hydroxyapatite is reduced, making the bones soft and weak (osteomalacia).

PMTs typically affect adults in their middle age, and they can develop in any bone or soft tissue region, including the base of the skull, the mouth cavity, the paranasal sinuses, the chest wall, the scapula, and the extremities.⁹ Nearly 300 PMT instances have been documented in the literature to date. According to a study in 2017, PMTs represent a single disease entity with identical SATB2, CD56, ERG, and somatostatin receptor 2A immunohistochemistry expression.¹⁰ Histologically, there is variable amount of ‘grungy’ calcified matrix with proliferation of bland spindle cells, hypocellularity and myxoid changes. PMTs resemble other mesenchymal tumours, like chondromyxoid fibroma, hemangiopericytoma, and solitary fibrous tumour. But, instead of being a tumour producing TIO, PMT is a specific neoplasm with an identical molecular profile but having various morphological types.^10,11 Rarely they show malignant histological features as well.

PMTs are often missed in clinical examination owing to their small size and lack of a typical anatomical location. Since they are rare, the diagnosis is often delayed due to the lack of consideration as a potential differential diagnosis even in subjects with osteomalacia.² The majority of patients with PMTs might have suffered debilitating osteomalacia for a long time before the tumor was anatomically pinpointed. A thorough scrutiny by clinical examination is of utmost importance to search for any subcutaneous soft tissue lesions that are often ignored just as in case that of a lipoma.¹² Estimation of FGF-23 levels can very well point towards an imbalance in the phosphate and bone metabolism. High levels of FGF-23 and low serum phosphate levels in an individual with normal PTH levels and renal parameters, with or without osteomalacia, is predictive of PMT. However, most of them require a PET/CT or MRI to localize the lesion, but ⁶⁸Ga- DOTOTAC PET CT scans are highly sensitive and specific to locate a PMT independently.^13,14

The possible differentials of renal phosphate wasting entities includes hereditary hypophosphatemic rickets with hypercalcuria, autosomal dominant and X-linked hypophosphatemic rickets, and Fanconi syndrome.¹⁵ Fanconi syndrome can appear in childhood or adulthood and is characterised by widespread malfunction of the proximal renal tubules. Aminoaciduria in Fanconi syndrome and hypercalciuria in hypophosphatemic rickets eases the differentiation from TIO. Even though it seems biochemically similar, autosomal dominant and X-linked hypophosphatemic rickets occurs in childhood, whereas TIO is presented and diagnosed in adulthood. A negative family history and detection of the tumor on ⁶⁸Ga- DOTOTAC PET CT points towards TIO.¹⁵

It is more important to persistently follow up such cases of osteomalacia with diligent efforts if the lesion is not localized. It may grow slowly and may get detected on serial follow up examination when coupled with estimation of FGF-23 levels, serum phosphorus, and other biochemical parameters. Above all, the most rewarding is the ⁶⁸Ga- DOTOTAC scan which pinpoints the exact sites of abnormal hormonal (somatostatin) expression^16,17 which when excised, brings an end to the agonizing symptoms.

4. Conclusion

The accurate detection of a phosphaturic mesenchymal tumor and the ensuing oncogenic osteomalacia can alleviate years of suffering. Removal of the tumor often results in pronounced clinical improvement and a striking reversal of biochemical parameters. Despite being an uncommon diagnosis, one should take phosphaturic mesenchymal tumor also into account in every setting of osteomalacia.

Funding statement

This original research or any of its authors were not been funded by any sponsors or corporates.

CRediT authorship contribution statement

Jijulal C.U.: Writing – original draft, devised the idea for the study, designed and drafted the figures, helped with the language, prepared the initial manuscript draft, and did the proof reading of the article. Sreeja Sreedharan: Writing – original draft, devised the idea for the study, designed and drafted the figures. Naveen P. Gopinath: contributed to the literature search. Sibin Surendran: Writing – original draft, contributed to the literature search, helped with the language, prepared the initial manuscript draft, and did the proof reading of the article. Gopinathan Patinharayil: Writing – original draft, devised the idea for the study, helped with the language, prepared the initial manuscript draft, and did the proof reading of the article. Muhammed Fazil V.V.: Writing – original draft, designed and drafted the figures. Nikhil K.V.: contributed to the literature search. Ram Sudhan S.: contributed to the literature search. All authors contributed to, reviewed and approved the final draft of the paper.