Phosphaturic mesenchymal tumor is first proposed by Weidner and Santa Cruz,[4] which is the common cause of tumor induced osteomalacia. In general, it is a benign, small lesion, which is difficult to detect, and malignant ones were less than 10% cases.[3] Primary site of PMT can be anywhere throughout the body, with 53% occurring in bone, 45% in soft tissue, and 2% in skin.[5–7] However, spinal PMT was rarely reported, especially Occipitocervical region.
In our review, totally 7 occipitocervical cases have been described in the English literature, including two cases we reported. Clinical data for these 7 patients are shown in Table 1. The mean age of these patients was 52.57 years (range 32–87 years) with a female predominance (all were female). Everyone suffered a long period of osteomalacia (mean time 2.86 years) before being ultimately diagnosed as PMT. In addition, all the patients underwent surgery, two of them were partial resection and both suffered recurrence. 2 patients received adjuvant radiotherapy. A total of 4 cases (57.14%) had recurrence during the follow-up.
Table 1
Clinical features of 7 cases with occipitocervical PMT published in English and our current study.
Author | Age (y) | Sex | Location | Recurrence/metastasis | Treatment | Duration of Osteomalacia | Follow-up |
Mulani M et al, 2017[8] | 48 | Female | left occipitotemporal bone | No | left retromastoid craniotomy and resection of tumor | 2 years | 1 months |
Folpe A et al, 2004[17] | 32 | Female | C1 vertebra | unresectable recurrence | surgery and radiotherapy | 4 years | 3 years |
Basu S et al, 2016[25] | 53 | Female | skull base and left basi-occiput | Multiple recurrence | Partial resection of tumor and retromastoid craniotomy | 2 years | 13 months |
Mishra T et al, 2019[26] | 52 | Female | left occipital bone | No | complete resection of the tumor and left retromastoid craniotomy | 2 years | 3 months |
Fatani HA et al, 2013[27] | 87 | Female | C2 vertebra | Multiple recurrence | Partial resection of tumor and C2 laminectomy | 6 years | unknown |
Our case 1 | 55 | Female | left occipitocervical region | No | anterior and posterior complete resection of tumor; occipital-cervical fusion | 1 years | 2 years |
Our case 2 | 41 | Female | Right C1-2 vertebra and clivus | local recurrence | posterior resection of tumor and radiotherapy | 3 years | 5 years |
Diagnosis of occipitocervical PMT is usually difficult in clinical practice, and the nonspecific symptoms such as a long-standing bone pain, muscle weakness or limited activity often interfere with the doctor's judgment. Then patients are often treated with calcium and phosphorus supplements. The lesion is not detected in the occipitocervical region until symptoms of nerve compression such as tinnitus[8] or a large mass occur. Our cases presented with a long-standing bone pain, headache and tongue deflection. And both patients could feel a large mass at the back of neck.
Biochemical indicators are mainly low serum phosphate, high ALP, low serum 1,25(OH)2D3, normal or slightly low serum calcium and high FGF-23. While there is also a few patients with normal lab findings.[6, 9, 10] In our study, the biochemical indicators of case 1 showed no abnormities which made diagnosis difficult.
In the early stage of PMT, the tumor is usually small and in obscure locations. Thus locating PMT is challenging, and the lesion often remained undetected by conventional tests. Many studies have confirmed the value of octreotide scan and PET/CT in early diagnosis.[1, 3, 11, 12] Technetium-99m octreotide scintigraphy can detect the expression of somatostatin receptors (SSTRs) and the accuracy rate is appropriately 60%.[1, 13] Jain A et al conducted a prospective study and used contrastenhanced 18Ffluorodeoxyglucose positron emission tomographycomputed tomography (FDG PETceCT) to locate the tumor. The result showed the sensitivity of PET-ceCT was 87.5%, and positive predictive value was 100%.[14] CT and MRI are valuable in analyzing the degree of bone destruction and the size of soft tissue mass. On CT scans, bone lesions are typically osteolytic, show a narrow zone of transition, and commonly contain internal matrix. On MRI examination, PMTs are usually T1 hyperintense, T2 mixed intensity, and uneven enhancement. Our two cases were detected easily through MRI and CT, because the tumor had grown too large which could be observed easily.
Histologically, majority of the PMT are benign and rich in spindle cells. The matrix demonstrates cartilaginous or myxomatous areas, abundant blood vessels, and metaplastic bone. And the tumor often lacks nuclear atypia and mitotic figures with low nuclear grade. Rarely, malignant PMT presented with increased cellularity, a high nuclear grade and excessive mitotic activity.[3, 15, 16] On immunohistochemical analysis, PMT has been scarce except for complementary studies performed to exclude other differential diagnoses. Folpe A et al[17] reported that desmin, S100 protein, CD34, and cytokeratins were usually negative. Recent studies showed a high sensitivity but limited specificity of FGF23 expression. Other newly-discovered markers such as SSTR2A, ERG, CD56, and DOG1 may be useful for diagnosis and differential diagnosis of PMT.[18]
At present, the treatment of PMT mainly includes medical therapy, surgical therapy, chemoradiotherapy and octreotide therapy. While surgical resection remains the main treatment option which can improve the abnormality of the biochemical indicators, and relieve the symptoms. The anatomy of the occipitocervical region is complex and contains many important structures such as vertebral arteries, nerve roots and spinal cord. Therefore, the operation on this site is difficult and delicate. In our cases, vertebral artery was enveloped by the mass and the surrounding normal tissue was severely compressed. We used 3D hawk-eye technology and computer assisted navigation system to carefully isolate and completely resect the tumor lesion. However, sometimes complete excision is not possible because the boundaries of the tumor are not well identified, and the surgeon had to perform partial resection. Sun Z et al reported about 5% patients experienced recurrence due to incomplete resection.[19] In our review, two patients of occipitocervical PMT undertook partial resection and both had recurrence (Table 1). Radiotherapy as a common adjuvant therapy has been shown to be effective in many cancers. One patient of our cases received postoperative radiotherapy, but had a local recurrence during follow-up. Folpe A et al[17] also reported a case of PMT in atlas. The patient undertook adjuvant radiotherapy, and suffered recurrence 3 years after surgery. Therefore, the effect of adjuvant radiotherapy was limited in occipitocervical PMT. In addition, calcium and phosphorus supplements may slightly relieve symptoms but cannot correct abnormal biochemical markers (hypophosphatemia).[20, 21] In our study, case 1 was initially treated with bisphosphonates to inhibit bone destruction, but the results showed that bisphosphonates had little control over tumor progression. Octreotide therapy is controversial now. Elston M et al[20] used preoperative octreotide therapy to treat oncogenic osteomalacia. The results showed a reduction in the serum FGF23, the serum phosphate initially increased but did not normalize. While Ovejero D et al reported that octreotide therapy is ineffective in treating tumor-induced osteomalacia in a short term.[22] Furthermore, other new therapies were also used to treat inoperable or recurrent PMTs including human monoclonal anti-FGF23 antibody,[23, 24] somatostatin analogues and peptide receptor radionuclide therapy (PRRT). Basu S et al used 177Lu-DOTATATE PRRT for the first time to treat patients with multiple recurrence. 3 months after treatment, the symptoms and indicators improved.[25] However, the long-term efficacy and safety of these therapies are unknown, and requires further research.