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\begin{document}

\title{Surgical and biochemical outcomes of phosphaturic mesenchymal tumors
causing tumor-induced osteomalacia in the head and neck region}



\author[1]{Yusuke Tsuda}%
\author[1]{Yoichi Yasunaga}%
\author[1]{Masanobu Abe}%
\author[1]{Kazuto Hoshi}%
\author[1]{Nobuaki Ito}%
\author[2]{Kenji Kondo}%
\author[1]{Koichi Okajima}%
\author[1]{Liuzhe Zhang}%
\author[1]{Hajime Kato}%
\author[1]{Naoko Hidaka}%
\author[1]{Sakae Tanaka}%
\author[1]{Hiroshi Kobayashi}%
\affil[1]{Tokyo University Hospital}%
\affil[2]{The University of Tokyo}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\selectlanguage{english}
\begin{abstract}
Objectives: We aimed to report the surgical outcomes of phosphaturic
mesenchymal tumors causing tumor-induced osteomalacia in the head and
neck. Design: A retrospective cohort study Setting: A tertiary care
academic hospital Methods: This study analyzed nine patients who
underwent surgical excision of phosphaturic mesenchymal tumors in the
head and neck region. The primary sites were two in the maxilla and
ethmoid sinus, and one in the intracranial, skull, parotid gland,
maxillary sinus, and nasal cavity in each patient. Outcomes were
compared with those in the extremities and trunk (n = 32). Results: Five
of nine patients (56\%) developed residual disease/local recurrence
associated with low serum phosphate level after initial surgical
excision. At the last follow-up, the biochemical parameters were
normalized in four of the five patients after re-excision without any
medication. The local recurrence/residual disease risk was significantly
higher for the head and neck compared with the extremities and trunk
(56\% vs. 25\%, p = 0.048). The rate of remission (normalized serum
phosphate without medication) at final follow-up was similar in both
groups after re-excision (head and neck vs. extremities and trunk, 86\%
vs. 73\%, p = 0.827). Conclusions: Phosphaturic mesenchymal tumor
resection in the head and neck region was challenging because of its
complex anatomy and proximity to the brain or other crucial organs,
which was associated with high local recurrence/residual disease rate.
However, biological remission was achieved in the majority of the
patients after re-excision.%
\end{abstract}%



\sloppy


\textbf{Original article}

\textbf{Surgical and biochemical outcomes of phosphaturic mesenchymal
tumors causing tumor-induced osteomalacia in the head and neck region}

\textbf{Abstract:}

\textbf{Objectives:} We aimed to report the surgical outcomes of
phosphaturic mesenchymal tumors causing tumor-induced osteomalacia in
the head and neck.

\textbf{Design:} A retrospective cohort study

\textbf{Setting:} A tertiary care academic hospital

\textbf{Methods:} This study analyzed nine patients who underwent
surgical excision of phosphaturic mesenchymal tumors in the head and
neck region. The primary sites were two in the maxilla and ethmoid
sinus, and one in the intracranial, skull, parotid gland, maxillary
sinus, and nasal cavity in each patient. Outcomes were compared with
those in the extremities and trunk (n = 32).

\textbf{Results:} Five of nine patients (56\%) developed residual
disease/local recurrence associated with low serum phosphate level after
initial surgical excision. At the last follow-up, the biochemical
parameters were normalized in four of the five patients after
re-excision without any medication. The local recurrence/residual
disease risk was significantly higher for the head and neck compared
with the extremities and trunk (56\% vs. 25\%, p = 0.048). The rate of
remission (normalized serum phosphate without medication) at final
follow-up was similar in both groups after re-excision (head and neck
vs. extremities and trunk, 86\% vs. 73\%, p = 0.827).

\textbf{Conclusions:}Phosphaturic mesenchymal tumor resection in the
head and neck region was challenging because of its complex anatomy and
proximity to the brain or other crucial organs, which was associated
with high local recurrence/residual disease rate. However, biological
remission was achieved in the majority of the patients after
re-excision.

\textbf{Key points:}

\textbf{} \selectlanguage{english}There have been a few reports on the surgical outcomes of
phosphaturic mesenchymal tumors causing tumor-induced osteomalacia in
the head and neck.

\selectlanguage{english}Tumor-induced osteomalacia is a rare and underreported condition
because treating clinicians are unaware of its clinical characteristics.
We highlighted our experience with Tumor-induced osteomalacia cases in
the head and neck regions.

\selectlanguage{english}Phosphaturic mesenchymal tumor resection in the head and neck region
was associated with high local recurrence/residual disease rate.

\selectlanguage{english}Before definitive resection, surgeons should discuss with their
patients the difficulty of obtaining clear margins due to the complex
anatomy.

\selectlanguage{english}Re-excision lead to biological remission in the majority of the
patients after re-excision.

\textbf{1 Introduction}

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder
caused by tumors that secrete fibroblast growth factor 23
(FGF23).\textsuperscript{1} Because of its role in renal phosphate
handling and vitamin D synthesis, TIO is associated with decreased renal
phosphate tubular reabsorption, hypophosphatemia, and low active vitamin
D levels. Patients are often affected by the muscular vulnerability and
bone pain for a prolonged time before diagnosis due to
osteomalacia.\textsuperscript{2,3}

The majority of tumors that cause TIO are classified as phosphaturic
mesenchymal tumors (PMTs).\textsuperscript{4} Head and neck regions were
the second most constant localization of tumor (26\%), next to the lower
limbs (46\%).\textsuperscript{2} Previous research on PMT in the head
and neck region was primarily case reports with short-term
follow-ups.\textsuperscript{5-7} Although comprehending the long-term
surgical result and the cases with residual/local recurrent tumors is
crucial for clinical administration, only a few reports have focused on
nonremission and recurrent PMT cases.\textsuperscript{8} There remains a
paucity of studies on long-term surgical and biochemical outcomes of PMT
in the head and neck area.

Therefore, the purpose of this study was to determine the long-term
surgical and biochemical outcomes of PMT in the head and neck region,
particularly in nonremission and recurrent cases. These outcomes were
also compared with PMT in the extremities and trunk.

\textbf{2 Patients and Methods}

We followed the STROBE reporting guidelines. Between 1998 and 2022, 67
patients with TIO were identified in our hospital's database. Among
them, nine patients with PMT in the head and neck regions who underwent
surgical excision were involved in this research. In comparison, 32
patients with PMT in the extremities and trunk who had surgical excision
were analyzed. Regarding the remaining 26 patients, tumors were not
detected by imaging studies in 18, the histology and clinical courses
were consistent with malignant tumors in 3, and only examinations were
conducted at our hospital in 5. These 41 patients' clinical records and
imaging studies were reviewed retrospectively.

Most patients suspected of having TIO were referred to the corresponding
department (oral and maxillofacial, orthopaedic, otolaryngology,
neurosurgery, etc.) from the endocrinology department. Multiple
examinations were carried out to identify the primary tumor, including
FGF23 venous sampling, 18-fluorodeoxyglucose positron emission
tomography with computed tomography (FDG-PET/CT),\textsuperscript{99m}Tc
bone scintigraphy, somatostatin receptor scintigraphy, or magnetic
resonance imaging (MRI).\textsuperscript{9}The diagnosis and
localization were made following a review of the histopathology and
radiology results with a multidisciplinary discussion. Serum phosphate,
alkaline phosphatase (ALP), and bone-specific alkaline phosphate levels
were measured regularly for postoperative monitoring. All the patients
were asked to visit the endocrinology department for follow-up at 2--3
months postoperatively and every 3--6 months thereafter.
Endocrinologists continued medical treatments for patients whose serum
phosphate levels did not return to normal after surgery. Biochemical
remission was defined as normalized serum phosphate and serum ALP levels
without any medication. Pathology findings were consistent with PMT,
showing the proliferation of bland spindle to stellate cells that were
immunohistochemically positive for FGF23.

FGF23 values were measured by an FGF-23 ELISA Kit, which exclusively
detects biologically active intact FGF23. FGF23 levels [?]30 pg/ml under
hypophosphatemic condition clearly differentiate FGF23-related
hypophosphatemia from hypophosphatemia due to other
causes.\textsuperscript{10,11} Immunohistochemistry for FGF23 was
conducted with monoclonal FGF23 antibody.

All patients underwent surgical excision of the tumor with the aim of
achieving R0 or R1 margin.\textsuperscript{12} Extended curettage was
used in patients with bone tumors at the extremity or trunk who were
expected to have functional impairment after surgery: the tumor was
removed with a curette, and the margin was expanded with high-speed
burring.\textsuperscript{13}

Case reports for cases 4\textsuperscript{14} and 5\textsuperscript{15}in
Table 1 are available elsewhere. The detailed results of these
multimodal tests for cases 2, 8, and 9 were reported in our group's
previous article (cases 2, 8, and 9 in the current study are equivalent
to cases 4, 1, and 27 in ref. 9).

Chi-square tests were used to compare the categorical variables between
the groups. Two-tailed probability (P) value of \textless{}0.05 was
considered to be statistically significant. To conduct statistical
analyses, R version 4.2.1 was used.

All procedures were carried out in accordance with the Declaration of
Helsinki's ethical standards and were approved by our institutional
ethical board {[}Ref. P2017016 and 2879{]}. All the patients provided
written informed consent.

\textbf{3 Results}

\textbf{3.1 Patient demographics, imaging, and biochemical work-up}

The patient details were included in Table 1. There were six male and
three female patients. The median age at diagnosis was 53 years
(interquartile range {[}IQR{]}, 41--63 years), the median follow-up
after initial resection was 64 months (IQR, 20--98 months), and the
median maximum tumor size was 20 mm (IQR, 11--36 mm).

The patient's symptoms on presentation to a doctor were bone or joint
pain in multiple locations. The time elapsed between the initial
patient's complaints and the diagnosis of TIO ranged from 5 to 126
months with a median delay of 72 months. Only 22\% of patients were
correctly diagnosed within 2 years, while 56\% were correctly diagnosed
between 5 and 10 years after the onset of symptoms. X-rays revealed
pseudofractures in all of the patients (Fig. 1a--e).
Whole-body\textsuperscript{99m}Tc bone scintigraphy demonstrated
increased uptake in multiple bones, including ribs, vertebrae, and
femur, in four available cases. The endocrine work-up revealed the
following laboratory findings: low serum phosphate (median 1.3 {[}IQR,
1.2--1.7{]} mg/dL, normal range, 2.7--4.6 mg/dL), high serum ALP (median
281 {[}IQR, 251--355{]} U/L, normal range, 38--113 U/L), normal to low
serum corrected calcium (median 8.7 {[}IQR, 8.5--9.0{]} mg/dL, normal
range, 8.8--10.1 mg/dL), and normal to high intact parathyroid hormone
(median 64 {[}IQR, 43--123{]} pg/mL, normal range, 15--65 pg/mL). The
serum FGF23 was elevated (median 241 {[}IQR, 194--3750{]} pg/mL). The
clinical signs, imaging studies, low serum phosphate levels, and
elevated serum FGF23 levels all pointed TIO.

To determine the localization of the primary tumor, systemic venous
sampling of FGF23 was performed in five patients. FGF23 levels were
highest in the internal jugular vein in two patients, the external
jugular vein, subclavian vein, and superior vena cava in one patient
each (Table 1). In all patients, MRI revealed a tumor in the head and
neck region. Somatostatin receptor scintigraphy was performed, which
enabled tumor visualization in all four available patients. FDG-PET/CT
revealed mild uptake (SUV max median 5.7, IQR 5.1--6.2) in the suspected
tumor.

\textbf{3.2 Surgical and biochemical outcomes}

Of the nine patients, four (44\%) underwent a biopsy before definitive
surgery, which confirmed the PMT diagnosis. Patients underwent surgical
excision of the tumor with R0 (n = 1) or R1 margin (n = 8). There was no
surgical complication. Residual/local recurrent tumors with low serum
phosphate were seen in five patients (56\%) after initial surgical
resection, including four residual and one local recurrent tumor. Of
these, four patients (80\%) underwent tumor re-excision, and serum
phosphate and FGF23 levels were normalized without any medication at the
final follow-up. Residual/local recurrent tumors were detected at median
19 months (range, 9--80 moths) form initial resection by imaging
studies. At the time of the last follow-up, eight patients (89\%) were
still alive, while one died from an acute myocardial infarction. The
four patients (44\%) were continuously recurrent tumor-free after the
initial surgery. Only one patient (11\%) was living with a recurrent
tumor after surgical excision and taking oral phosphate and activated
vitamin D.

\textbf{3.3 Comparison with outcomes of PMT in the extremity and trunk}

The patient details were shown in Table 2. The rate of residual
disease/local recurrence with low serum phosphate was significantly
higher in cases at the head and neck (56\%) compared with cases at the
extremities and trunk (25\%, 8 of 32, p = 0.048). Re-excision was
performed in 25\% of patients (2 of 8) with extremity or trunk tumors
which is lower compared with that in the patients with head and neck
tumors (80\%, 4 of 5). At the last follow-up, the rate of biochemical
remission without medication was similar in both groups (89\% of the
patients with head and neck tumors and 75\% of patients with extremity
and trunk tumors, p = 0.827). At the last follow-up, medical treatment
was continued in one patient (11\%, 1 of 9) with a head and neck tumor
and eight (25\%, 8 of 32) with extremity and trunk tumors.

\textbf{3.4 Case presentation}

\textbf{Case 1 in Table 1:}

Here, we present a representative patient with a residual tumor. A
38-year-old male was referred to the evaluation of worsening pain in his
knee, hips, and lower back without an injury history. The medical
history of the patient was unremarkable. On laboratory results, low
serum phosphate (1.3 mg/dL), high ALP (524 U/L), intact parathyroid
hormone (117 pg/mL), and FGF23 (660 pg/ml) levels were observed.
Functional imaging with somatostatin receptor scintigraphy showed
increased uptake in the nasal region (Fig. 2a). A contrast-enhanced
maxillofacial area CT revealed a mass in the nasal cavity (Fig. 2b and
c). An incisional biopsy was performed, and microscopic examination
revealed a vascular-rich tumor composed of FGF23-positive bland spindle
cells (Fig. 2d). A PMT diagnosis was made. Two weeks after the initial
biopsy, endoscopic resection of the tumor was performed. However, low
serum phosphate and high FGF23 levels persisted, and MRI revealed a
residual tumor at the left cribriform plate one year after resection
(Fig. 2e and f). After the patient underwent re-excision under the
endoscopic endonasal technique, the serum phosphate levels returned to
normal. The last follow-up was negative for tumor recurrence or residual
tumor.

\textbf{4 Discussion}

We have reported the surgical and biochemical outcomes for head and neck
TIO. PMT resection in the head and neck region was associated with high
local recurrence/residual disease rate (56\%), which was significantly
higher than that of the extremities and trunk (25\%). However,
biochemical remission was achieved in the majority of the patients after
re-excision at the last follow-up (89\%, 8 out of 9).

Most of the previous reports concerning the head and neck TIO were small
case series often mixed with other sites, which had short-term
follow-ups within two years after surgical
excision.\textsuperscript{5-7,16,17} Pal et al. reported surgical
excision in 30 cases TIO in various sites, which resulted in remission
in 73\% of the patients, whereas disease persistence and tumor
recurrence in 18\% and 9\% of the cases,
respectively.\textsuperscript{18} Zhu et al. analyzed 43 patients with
sinonasal tumors, including PMT, odontogenic fibroma, and
hemangiofibroma, which were associated with TIO.\textsuperscript{19} In
the series, a high local recurrence rate or nonremission was found
(12\%). The other report illustrated the seven patients with TIO in the
paranasal sinus, intracranial, and maxilla who underwent surgical
excision.\textsuperscript{20} They demonstrated that four of seven
(57\%) had persistent illness after surgical removal, and three patients
were managed by external beam radiation treatment for recurrent tumors.
Consistent with these reports, our data demonstrated a great residual
disease/local recurrence rate in the head and neck PMT. However, in most
of our patients, biochemical remission was attained after re-excision
without radiation treatment. We believe that re-excision of the
residual/local recurrent tumor without radiation therapy is a practical
treatment option. In contrast to our findings, Li et al. reported that
the refractory rate was the lowest in head and neck tumors (7.5\%)
compared to other sites.\textsuperscript{8} However, they did not state
the details of localization of the tumor, surgical methods, and
complications after surgery for the head and neck tumors. In our
residual/recurrent cases, craniotomy was conducted due to the proximity
of the brain in three cases. The surgical process, surgical margin, and
localization of the tumor presumably contributed to the differences in
outcomes.

Complete surgical excision with wide margins was the cornerstone of PMT
management.\textsuperscript{21,22} The main surgical challenge of
resection of head and neck PMT is the difficulty of obtaining a clear
margin because of the anatomical complexity and proximity of the brain
or other important organs. Previous studies showed that soft tissue PMT
with an irregular boundary observed on imaging tended to infiltrate into
subcutaneous fat.\textsuperscript{21} Furthermore, bone PMT demonstrated
invasion into cancellous and cortical bone.\textsuperscript{22} These
findings suggest that in patients with these imaging features, resection
of infiltrative margin in soft tissue tumor or resection of thinned
cortical bone may be required to reduce the risk of local
recurrence/residual disease. However, excessive removal of the
surrounding tissues may increase the risk of surgical morbidity,
particularly in cases of head and neck PMT. Surgeons need to balance the
risk of surgical morbidity and local recurrence/residual disease.

TIO is a rare and underreported condition because treating clinicians
are unaware of its characteristic, clinical, and biochemical
profiles.\textsuperscript{3} Through this research, we highlighted our
experience with TIO cases including the head and neck regions. A
significant time gap between the initial presentation until the
diagnosis existed even in the presence of severe symptoms in our series.
Other challenges included the difficulty of distinguishing PMT from
other incidental findings on imaging studies. Especially in the head and
neck area, apical periodontitis was encountered, which was suspected to
be a tumor that caused TIO (Fig. 3a--f). Furthermore, X-linked
hypophosphatemic rickets/osteomalacia is one of the possible
differential diagnoses in patients with osteomalacia who have abnormal
findings in the alveolar bone area, which can lead to a variety of
dental complications, including apical
periodontitis.\textsuperscript{23} These findings will raise awareness
and provide valuable insights into the treatment of issues associated
with this rare disease in the head and neck region.

We would like to acknowledge the limitations of our study. First, this
study involving a heterogeneous and small group of patients. Second, our
study is a retrospective review and there are selection, indication, and
expertise biases concerning both the initial surgery and subsequent
procedures. Third, patients were treated over two decades, and we were
unable to adjust for important confounders, including evolution in
treatment strategies and medical/surgical/imaging management/techniques.
A histopathology and radiology review at an institutional
multidisciplinary board meeting, we believe, has reduced these biases.

In conclusion, PMT in the head and neck area demonstrated a high local
recurrence/residual disease rate. However, biochemical remission was
achieved in most patients at the last follow-up. Before definitive
resection, surgeons should discuss with their patients the difficulty of
obtaining clear margins due to the complex anatomy of the region and the
proximity of important organs.

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\textbf{Figure legends}

\textbf{Figure 1.}

An 87-year-old man with a phosphaturic mesenchymal tumor in the ethmoid
sinus (case 9). \textbf{a)} Radiograph of the right knee demonstrates
coarse trabecular bone involving distal femur, proximal tibia, and
proximal fibula with the presence of pseudofractures.\textbf{b)}
~Radiograph of the left humerus demonstrates pseudofractures.\textbf{c)}
A lumbar spine radiograph reveals diffuse osteopenia with variable
decreases in vertebral body heights. \textbf{d)}\textsuperscript{99m}Tc
bone scintigraphy reveals increased tracer uptake in multiple ribs,
vertebral bodies, the left humerus, the right distal femur, the right
proximal tibia, and the left distal tibia, indicating multiple
pseudofractures.~\textbf{e)} Coronal brain MRI reveals a lobulated mass
(white arrow) in the ethmoid sinus with extension to the skull base.

\textbf{Figure 2.}

A 38-year-old man underwent excision of a nasal cavity PMT (case
1).\textbf{a)} Somatostatin receptor scintigraphy reveals increased
uptake in the tumor region (white arrow). The tumor (white arrow) is
visible in the nasal cavity on preoperative \textbf{b)} axial and
\textbf{c)}coronal CT images. \textbf{d)} Pathological examination
reveals a vascular-rich tumor composed of bland spindle cells that were
immunohistochemically positive for FGF23 (inset). T1-weighted
contrast-enhanced MRI of the nasal cavity \textbf{e)} axial
and\textbf{f)} coronal views show a recurrent tumor (white arrow head).

\textbf{Figure 3.}

A 60-year-old man underwent excision of a left mandibular lesion
suspected of being a tumor that caused TIO. Histological findings showed
dense immunocompetent cell infiltration, which was consistent with
apical periodontitis. A radiolucent area (white arrow) is visible on
orthopantomography \textbf{a)} and periapical radiographs \textbf{b)} at
the mandibular \#5 teeth area. Preoperative CT images \textbf{c)} axial
and \textbf{d)} sagittal show bone destruction in the mandibular region
(white arrow). \textbf{e)} An enhanced mass on preoperative T1-weighted
contrast-enhanced MRI (white arrow). \textbf{f)} FDG-PET/CT presents
increased uptake in the mandibular area (white arrow).

\textbf{Hosted file}

\verb`FinalFile_TIO_Head_and_neck_Table.docx`  available at \url{https://authorea.com/users/643818/articles/656947-surgical-and-biochemical-outcomes-of-phosphaturic-mesenchymal-tumors-causing-tumor-induced-osteomalacia-in-the-head-and-neck-region}

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