A case of malignant pheochromocytoma with neurofibromatosis type 1 having difficulty in differentiating spinal tumor

Introduction Neurofibromatosis type 1 is a hereditary condition often associated with pheochromocytomas but rarely with malignant pheochromocytomas. Neurofibromatosis type 1 is often associated with bone lesions, which complicates the distinction between malignant and benign tumors. Case presentation A 46‐year‐old man with a medical history of neurofibromatosis type 1 presented with right abdominal pain. Computed tomography revealed a right adrenal tumor, and metaiodobenzylguanidine scintigraphy showed accumulation in the right adrenal gland and thoracic vertebrae. He was diagnosed with pheochromocytoma, and a right adrenalectomy was performed. After surgery, a bone biopsy was conducted on the spinal lesion, confirming metastasis of pheochromocytoma, prompting irradiation. After that, lung and liver metastases emerged, and chemotherapy with cyclophosphamide, vincristine, and dacarbazine was initiated; however, the disease progressed, and he died 11 months after surgery. Conclusion We report a case of malignant pheochromocytoma associated with neurofibromatosis type 1 in which bone metastasis was difficult to diagnose.


Introduction
NF1 is the most prevalent autosomal-dominant inherited disorder and is associated with various benign and malignant tumors. 1,2Pheochromocytomas occur more frequently in patients with NF1 than in the general population, 3 with malignant occurrences being rare.
The 5-year overall survival rate for malignant pheochromocytomas is 55-75%, signifying a generally poor prognosis. 4,5The frequency of bone metastasis is high in patients with malignant pheochromocytoma. 5,6Some spinal tumors, including neurofibromatosis and schwannoma, are relatively common in 13-65% of patients with NF1. 1,7,8It can be difficult to distinguish spinal tumors with NF1 from other malignant bone tumors, including metastasis.This case report describes a patient with malignant pheochromocytoma associated with NF1 who presented with thoracic vertebral metastases.

Case presentation
A 46-year-old male visited a physician with complaints of right-sided abdominal pain.Right adrenal pheochromocytoma and multiple bone metastases were suspected, prompting a visit to our hospital.He had a history of NF1 and a compression fracture of the thoracic vertebrae, possibly due to a spinal tumor.At the time of visit, he was taking 8 mg of doxazosin, and his blood pressure was normal without any symptoms.Numerous caf e-au-lait spots and neurofibromas were observed on the left forearm and back.Levels of noradrenaline and dopamine in the blood, and metanephrines and normetanephrine in 24-h urine storage tests were high (Table S1).
Abdominal contrast CT revealed a right adrenal mass, 93 mm in size (Fig. 1a).123I-MIBG scintigraphy also showed multiple accumulations in the right adrenal mass, 11th thoracic vertebral body, and 12th thoracic vertebral arch (Fig. 1b,c) and weak abnormal accumulation in the right iliac bone.FDG-PET showed accumulation in the adrenal mass (SUVmax 4.0) (Fig. 1d) and the 11th thoracic vertebra (SUVmax 5.3) (Fig. 1e).MRI showed the spinal cord tumor was accompanied by dural sac extension, suggesting a schwannoma of NF1 origin (Fig. 1f).Using imaging alone, it was difficult to differentiate whether the spinal tumor was metastatic or a neurogenic tumor of NF1 origin.
Although a spinal biopsy was necessary to confirm the diagnosis, we opted for adrenalectomy due to the potential risk of a hypertensive crisis and for tumor reduction.The operation was initiated in the supine position, and a chevron incision was placed.During the open right adrenalectomy, minor adhesions of the tumor to surrounding tissues resulted in a surgery time of 5 h 32 min, with a blood loss of 320 mL.Pathology was mostly positive for chromogranin A, leading to a diagnosis of pheochromocytoma (Fig. 2a-c).The Ki-67 labeling index was 8.8%, and the Pheochromocytoma of the Adrenal gland Scaled Score (PASS) 9 was 4 points, indicating malignancy (Fig. 2a-c).The Grading System for Adrenal Pheochromocytoma and Paraganglioma 10 score was 5 points, indicating moderately differentiated type.Pathological margins were negative.
One month postoperatively, a CT-guided needle biopsy confirmed pheochromocytoma metastasis in the 11th thoracic spine lesion (Fig. 2d-f).He continued taking doxazosin, and there were no complications associated with the biopsy.The patient's clinical course is shown in Figure 3. Radiation (30 Gy/10 fr) was administered to the 11th-12th thoracic spine metastases.Radionuclide therapy was not covered by insurance at the time of treatment, and the patient did not request it.Three months after surgery, the patient was diagnosed with bone metastasis due to an increase in the right iliac lesion and was treated with both irradiation (30 Gy/10 fr) and denosumab.Five months after surgery, liver and lung metastases appeared, and chemotherapy with CVD was administered.Six months after surgery, muscle weakness in the lower limbs developed, and MRI indicated worsening spinal metastasis (Fig. 4a,b).Additional irradiation (30 Gy/10 fr) was performed on the 5th-9th thoracic vertebral lesions.The level of serum noradrenaline and urinary normetanephrine did not become negative after surgery and tended to increase as the disease progressed (Fig. 3).Cancer clinical sequence testing with the OncoGuide TM NCC Oncopanel System (Sysmex Corporation, Kobe, Japan) was performed.However, neither somatic nor germline mutations, including NF1, were detected.Five courses of CVD were administered, yet the disease progressed, and the patient died 11 months after surgery.

Discussion
NF1 is an autosomal-dominant disorder characterized by skin lesions like neurofibromas and caf e-au-lait spots and various bone, eye, and nervous system manifestations. 1Although we could not detect NF1 mutations in this case, next-generation sequencing could not detect mutations in 7.0% of NF1 cases in the previous report. 11NF1 is a relatively common genetic disorder, occurring in 1 in about 2600-4950 births worldwide. 2,12Various benign and malignant tumors occur, with a high rate of neurogenic tumors. 1 Pheochromocytomas manifest in 0.1%-5.7% of patients with NF1, 3 with a rate of malignant transformation comparable to general malignant   2 (a-c) A pathological specimen after total adrenalectomy (H&E (a), chromogranin A (b), and Ki67 staining (c), respectively), positive for chromogranin A, suggesting pheochromocytoma and Ki-67 labeling index was 8.8%.(d-f) A pathological specimen of CT-guided needle biopsy of a spinal tumor (H&E (d), chromogranin A (e), and Ki67 staining (f), respectively) was positive for chromogranin A, suggesting metastasis of pheochromocytoma and Ki-67 labeling index was 10%.
Fig. 3 Clinical course after right adrenalectomy.Arrowheads were metastases.The dotted line was the upper limit of normal levels for serum noradrenaline, urinary metanephrine, and normetanephrine.Urinary metanephrine and normetanephrine were measured by 24-h urine storage test.
pheochromocytomas. 1,3A previous report detailed 10 cases of metastatic pheochromocytoma associated with NF1, with a median age of 46 years and median tumor size of 6 cm. 13 The most common site of metastasis was the bone (50%), followed by the lung and liver, 13 as with general malignant pheochromocytoma. 6F1 is often associated with bone involvement, which is important in differentiating it from bone metastasis.Patients with NF1 have a relatively high frequency of spinal tumors. 1,7,8With respect to histology, most spinal tumors with NF1 are neurofibromas, rarely schwannomas. 14Malignant peripheral schwannomas affect 4.6% of patients with NF1, 55% of which involve the trunk. 15n this case, a compression fracture due to a spinal tumor was observed before diagnosing pheochromocytoma, and schwannoma with NF1 was first suspected based on imaging findings, as dural sac extension was observed on MRI.MIBG scintigraphy revealed abnormal accumulation, which increased the possibility of pheochromocytoma metastasis.Nevertheless, MIBG, including 123I and 131I, is not sensitive enough for malignant pheochromocytoma, and Timmers reported a sensitivity of 65% in SDHB mutation-positive cases. 16Reports exist of 123I-MIBG accumulation in juxta-adrenal schwannoma. 17Therefore, the possibility that the spinal tumor was also a schwannoma in this case could not be excluded.
PET-CT may be useful in localizing metastatic pheochromocytoma. 18Previous review showed significant differences in mean SUVmax between benign neurofibromas and malignant peripheral schwannomas in patients with NF1, and the general cut-off value of SUVmax was 3-4. 19In this case, the bone SUVmax value of the supine lesion was 5.3, and distinguishing between metastatic or benign tumors remained challenging.
In conclusion, we report a rare case of NF1-associated malignant pheochromocytoma with bone metastasis.In this case, it was difficult to diagnose whether the spinal tumor originated from NF1 or was a pheochromocytoma metastasis.Malignant pheochromocytomas have a poor prognosis; hence, prompt diagnosis of metastases is important.

Fig. 1
Fig. 1 (a) Abdominal contrast CT shows a right adrenal mass (arrow) of 93 mm in size with internal hemorrhage and necrosis.(b, c) 123I-MIBG scintigraphy shows multiple accumulations in the right adrenal mass (arrow) (b), 11th thoracic vertebral body, and 12th thoracic vertebral arch (arrowheads) (c).(d, e) FDG-PET CT scan shows accumulation in the adrenal mass (SUVmax 4.0) (arrow) and thoracic vertebra (SUVmax 5.3) (arrowhead).(f) MRI T2-weighted sagittal image shows loss of normal fatty marrow and high signal in the 11th thoracic vertebra (Arrowhead), with dural sac dilatation at the level of the 11th and 12th thoracic vertebra.

Fig. 4
Fig. 4 MRI of a patient with onset of lower extremity muscle weakness.Fat-suppressed T2-weighted image showing multiple high-signal areas in the spine.(a) It extends into the spinal canal in the 5th-8th thoracic vertebrae (arrows).(b) A known fracture of the vertebral body in the 11th thoracic vertebra (arrowhead).