Pheochromocytoma Metastasing to the Jaw: Review of the Literature and New Case

Abstract

Pleochromocytoma is a benign neuroectodermal tumor of the adrenal medulla. Ten to thirty percent of these tumors become metastatic. The bone is the most frequent site for metastasis but jaw involvement is reported rarely. A case of mandibular involvement is reported and a literature review in this topic is presented. Preoperative management of these patients undergoing general anesthesia is not a routine practice in maxillofacial surgery, so this topic is also is explained.

Introduction

Pheochromocytoma is a being neuroendocrine tumor of the adrenal medulla. Ten percent are bilateral or extra-adrenal in location [1]. Its products “catecholamines” have grave systemic manifestations with the most symptoms in the cardiovascular system. Cerebral hemorrhage and pulmonary edema are the other important events related to this disease [2]. Palpitation, intermittent high blood pressure not responding to routine drugs, fatigue, and sweating are symptoms of this disease. This entity should include in the differential diagnosis of hypertension in children [3].

Between 10 and 30% of pheochromocytoma may metastasis to the other organs, hence become malignant [4]. However, in the latest update of neuroendocrine tumors classification published by WHO in 2017, the term “malignant pheochromocytoma has been replaced by metastatic pheochromocytoma” because of this biologic behavior [5].

Pheochromocytoma metastasis mainly involves the bones, but jaw metastasis is extremely rare.

Case Report

The patient was a 45-year-old female, with expanding painless mass of the left mandible (Fig. 1). She had uncontrolled hypertension (BP (19/11), HR 111) and excess sweating, anemic with hemoglobin 8 g/dl, and hematocrit 29.4%. There was a history of laparotomy surgery to remove the 10-cm mass (pheochromocytoma) from the right adrenal gland 2 years ago. In physical examination, there were laminar striations in abdominal skin, so Cushing syndrome was also suspected.

Fig. 1.

Extraoral photograph

In a panoramic view, there was an osteogenic tumor of the left mandible with sunburst periosteal reaction.

Under local anesthesia, an incisional biopsy was taken. The histopathological finding revealed that the round cells were solid or arranged in nest, trabeculae, or cord, with high vascularization and hyalinized stroma. The cytoplasm of tumor cells was eosinophilic. The round nuclei were varied in size. Immunohistochemical staining demonstrated that tumor was chromogranin A (+), S100 (+), vimentin (+), myogenin (−), actin (−), melan A (−), CD138 (−), CD31 (−), Sox10 (−), and HMB45 (−).

The Ki67 index was 7% (Fig. 2).

Fig. 2.

Histopathological finding. a Hematoxylin and eosin stain (magnification × 100). b Chromogranin A (magnification × 200). c Vimentin (magnification × 200). d S100 (magnification × 100). e Ki67 (magnification × 200)

The pathologist report was paraganglioma or pheochromocytoma metastasis. Since these two tumor types cannot be differentiated based on histologic findings, the anatomic location of the primary tumor (adrenal or extra-adrenal) is critical. Based on a combination of histopathologic and clinical findings, malignant pheochromocytoma became the diagnosis.

Paraclinic Evaluation

Forty-eight hours after slow IV injection of 1.7 mCi of iodine-131-MIBG, whole-body scan and SPECT/CT from the skull, thoracic, and abdominopelvic regions were performed. Physiologic radiotracer uptake was noted in the salivary glands, liver, spleen, and genitourinary tract. Abnormal tracer uptake was noted in the left mandible (Fig. 3).

Fig. 3.

MIBG scintigraphy

On the SPECT/CT scan images, abnormal tracer uptake was noted in the left mandible with the destruction of adjacent structures. Also in CT scan images, a lytic lesion in left frontal bone in the skull and multiple nodes in both lungs were noted. Sonography and CT scan of the abdomen were performed to roll out the recurrence. Twenty-four-hour urine analysis with special emphasis on catecholamines and their metabolites was VMA 60 mg normal (nl): less than 13.6 mg; metanephrine 145 mcg, nl: 5–330 mcg; and normetanephrine 2133 mcg, nl: 5–600 mcg.

Based on increased urine normetanephrine, tumor secretions were mainly norepinephrine.

Based on physical examination, the paraneoplastic syndrome was considered, so serum cortisol level and calcium, phosphate, alkaline phosphatase, and PTH level were checked. Serum cortisol level was high (40.9 mcg/dl). Normal laboratory range for serum cortisol was 4.62–19.5 mcg/dl.

Preoperative Medical Preparation

Two weeks before surgery, an irreversible noncompetitive α-blocker (phenoxybenzamine) was started. Hemoglobin raised to 11.2 and HCT became (37.7%). Blood pressure before surgery was 14/8. High-sodium diet and fluid intake were started to improve the blood volume and prevent severe hypotension after tumor removal. In consultation with a cardiologist, great emphasis was on every attempt to reduce the operation time.

Surgery

Under nasotracheal intubation, composite resection of the lesion through the extraoral approach was done. The titanium reconstruction plate was used for aligning proximal and distal segments after resection. The orthograde submental flap was used to replace the omitted intraoral mucosa (Fig. 4). A nasogastric tube was used, and the patient was extubated and sent to the ICU.

Fig. 4.

a Resected mass. b Orthograde submental flap is used to cover the reconstruction plate. c Postoperative OPG

Postoperative Management

ICU stay was 5 days and after that, she was transferred to the ordinary surgery unit. She was discharged from the hospital, 3 days after that (total hospital stay = 9 days).

Postoperative Medical Management

BP was 150/80, the night after the operation.

According to the postoperative consultation, the following drugs were prescribed:

1. Tab clonidine 0.2 mg Bid

2. Tab prazocin TDS (α1—adrenergic receptor blocker)

3. Amp labetalol 0.25 mg/kg (α- and β-blocker)

Discussion

Pheochromocytoma in dentistry is disused on three occasions: first, dental management of pheochromocytoma in patient with hypertension who needs local anesthesia without vasoconstrictors and, second, in patients with oral manifestations of multiple endocrine neoplasia (MEN) [6]. Third, undiagnosed patients with elevated blood pressure and tachycardia undergoing general anesthesia for oral surgery [7].

Although the bone is the most frequent site for metastasis of pheochromocytoma, head and neck involvement is rare. Search of PubMed for English Language articles for tumors with positive chromogranin A staining is summarized in Table 1 [8–14].

Table 1.

Mandibular involvement by tumors with positive staining for chromogranin A (without current case)

Reference	Year	Primary source of tumor	Appropriate term	Catecholamine state
Peters et al. [14]	1991	Not found	Primary neuroendocrine tumor	Normal (non functional)
Coleman et al. [13]	1996	Not found	Primary neuroendocrine tumor	Not mentioned
Field et al. [12]	1998	Organ of Zuckerkandl (near the aortic bifurcation)	Malignant paraganglioma	Elevated
Yanagi et al. [11]	2002	Right adrenal	Metastatic pheochromocytoma	Normal
Sugawara et al. [10]	2015	Duodenum	Malignant paraganglioma	Normal
Sinha et al. [9]	2017	Not found	Primary neuroendocrine tumor	Normal
Stanek et al. [8]	2018	Abdomen (adjacent to inferior vena cava)	Malignant paraganglioma	Normal

Cases that maxilla or mandible was involved by chromogranin cells were listed (7 cases). The primary source of the tumor was searched. In the cases the extra-adrenal gland was the primary source, the term malignant paraganglioma was the term of choice for the metastatic lesion. If the primary source was the adrenal gland, the term metastatic pheochromocytoma was suitable for jaw lesion. In the situation that the primary source of the tumor was not found, the term “primary neuroendocrum tumor of the jaw” was chosen. All of the mandible was involved.

Including the case presented in this article, two pheochromocytoma cases metastasing to the jaws were found (Table 2). Although Fields et al. published the first case of malignant pheochromocytoma with metastasis to the mandible, however, the tissue of origin was the organ of Zuckerkandl [12]. Based on location, it is actually an extra-adrenal paraganglioma so the suitable term is malignant paraganglioma.

Table 2.

Demographic information of three patients with pheochromocytoma metastasing to the mandible

	Age	Sex	Site	Size (cm)	Laparotomy	MIBG (other than mandible)	Radiographic sign	Reconstruction	Hospital stay (days)	Reference
1	59	M	Ramus-midbody (right)	6 × 7	Negative (initial manifestation was mandibular swelling)	Liver-lumbar vertebra-ribs sacroiliac joins	Sunburst	?	?	11
2	47	F	Ramus-midbody (left)	7 × 8	Positive (2 years ago)	Lung temporal bone	Sunburst	Reconstruction plate + submental flap	9	Current article

Based on electrolyte and cardiac instability of these patients during surgery, we choose a pedicled flap (submental flap) combined with a reconstruction plate for reducing the operation time. Neuroendocrine tumors secrete hormone-like materials in 25–30% of cases (carcinoid syndrome) [15]. Secretory tumors are more complicated in management than in non-secretory ones [16].

Conclusion

Metastasis should be included in the differential diagnosis of sunburst periosteal reaction of the mandible in the patient with refractory hypertension.