CLINICAL REPORT
Malignant Pheochromocytoma Presenting as Incapacitating Bony Pain Marilyn Tan, MD*; Carlos A. Camargo, MD†; Amirkaveh Mojtahed, MD‡; Fred Mihm, MD§ *Department of Internal Medicine, †Department of Endocrinology, ‡Department of Pathology, § Department of Anesthesia, Stanford University Medical Center, Stanford, California, U.S.A.
n Abstract: Among adrenal incidentalomas, pheochromocytomas are rare. Malignant pheochromocytoma is even less common, and it typically presents with classic hormonal symptoms, such as palpitations, labile blood pressures, and headaches. Bony metastasis usually occurs late in disease, but we report an unusual case of incapacitating bony pain as the initial presentation of malignant pheochromocytoma. Our patient is a 70-year-old woman with neurofibromatosis type 1 and a history of primary hyperparathyroidism, who tested negative for the ret mutation. She came to medical attention with chest pain and palpitations and was incidentally found to have an adrenal mass. Serum and urine testing was consistent with pheochromocytoma. Her blood pressure was easily controlled as she awaited elective adrenalectomy; however, she quickly developed severe, diffuse bony pain. She represented with hypercalcemia, spontaneous fractures, and incapacitating pain that required such high doses of pain medications that she had to be intubated. Further imaging and bone marrow biopsy confirmed metastatic neuroendocrine tumor. She received one round of chemotherapy with no change in her bony pain, which was her primary Address correspondence and reprint requests to: Marilyn J. Tan, MD, Stanford University Medical Center – Medicine, 300 Pasteur Drive Grant S101/MC 5109, Stanford, CA 94305, U.S.A. E-mail:
[email protected]. Submitted: April 11, 2011; Revision accepted: July 6, 2011 DOI. 10.1111/j.1533-2500.2011.00499.x
2011 The Authors Pain Practice 2011 World Institute of Pain, 1530-7085/12/$15.00 Pain Practice, Volume 12, Issue 4, 2012 286–289
complaint. Unfortunately, her treatment options were limited by the heavy sedation required for comfort, and in the end, it was her bony pain rather than hormonal symptoms that made her disease untreatable.n Key Words: pain, intractable, cancer
INTRODUCTION Pheochromocytoma is found in 4% of those with adrenal incidentalomas. The incidence in the general population is 1 per 100,000 persons per year or less, and approximately 10% of those are malignant.1 The annual age-adjusted prevalence of malignant pheochromocytoma in the United States is 0.3 to 0.7 cases per 1 million.2 It is also known to be associated with other conditions, such as neurofibromatosis type 1 (NF1) and multiple endocrine neoplasia type 2 (MEN 2). Metastatic disease commonly presents with hormonal symptoms, such as the classic headache, sweating, and tachycardia. Bony metastases usually occur later in disease,3 and in 1987, Lynn et al.4 reported a series of 6 cases of malignant pheochromocytoma presenting with bone pain. We report an unusual case of incapacitating bone pain as the initial presentation for malignant pheochromocytoma.
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CASE PRESENTATION A 70-year-old woman was admitted for bone pain and hypercalcemia. She had a history of NF1 with truncal and limb neurofibromas, axillary freckling, and cafe´ au lait spots. She also had multiple family members with the same disease, including a sister who had a pheochromocytoma at autopsy. Seven years prior to admission, she was diagnosed with primary hyperparathyroidism, and pathology of the resected glands revealed 2 parathyroid adenomas. She and her entire family had undergone testing for the ret mutation, which was negative in every person. Eight weeks prior to admission, she complained of new onset back pain. Six weeks prior to admission, she presented to a hospital with 24 hours of severe palpitations, feelings of her ‘‘heart racing,’’ and new onset shortness of breath. Systolic blood pressures in the emergency department ranged from 140 to 170 mm Hg. Electrocardiogram demonstrated sinus tachycardia with a heart rate of 130 bpm. D-dimer was elevated, and calcium was within normal limits. With suspicion for pulmonary embolism, a computerized tomography of the chest was performed, and there was an incidental finding of a 5.5 cm heterogeneous right adrenal mass suspicious of neoplasm. Twenty-four hour urine testing revealed urine normetanephrine of 36,854 lg/dL (normal range 50 to 650), urine normetanephrine-to-creatinine ratio of 42,656 lg/gCR (normal range 0 to 400), urine metanephrine of 2374 lg/dL (normal range 30 to 350), and urine metanephrine-to-creatinine ratio 2747 lg/ gCR (normal range 0 to 300). Serum epinephrine by high-performance liquid chromatography was 273 pg/mL (normal range 10 to 200), and norepinephrine was 3239 pg/mL (normal range 80 to 520). A diagnosis of unilateral pheochromocytoma was made. She was started on low-dose phenoxybenzamine monotherapy in preparation for surgery, with subsequent systolic blood pressures from 110 to 120 mm Hg at home. Ten days later, during urologic pre-operative evaluation for her elective adrenalectomy, routine laboratory testing showed a new elevated serum calcium of 12 mg/dL. The patient complained of nausea, sleepiness, constipation, and worsened diffuse bone pain, particularly in her sternum and hips. Her family reported that she complained of significant sternal pain after exerting herself washing dishes. Further testing
demonstrated normal levels of 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D, undetectable calcitonin, undetectable PTHrP, and very low PTH (< 3 pg/mL). The following week, her bony pain became unbearable despite large doses of naproxen, tramadol, carisoprodol, alprazolam, and fosamax. She was re-admitted to the hospital for pain management, and she was started on a fentanyl patch and high doses of hydromorphone, making her somnolent soon after. She was also found to have a corrected calcium of 12.9 mg/dL and an elevated alkaline phosphatase of 417 U/L. Her acute hypercalcemia was presumably from a destructive process in the bones. She was treated with bisphosphonates, IV fluids, and calcitonin, but even after her calcium normalized, her debilitating pain persisted. Magnetic resonance imaging revealed lytic lesions in her ribs, sternum, spine, and sacrum. CT thorax demonstrated a sternal fracture (Figure 1), multiple subcentimeter pulmonary nodules suspicious of metastatic disease, and a single 1.4-cm liver lesion. A random bone marrow biopsy of her hip revealed that the bone marrow was infiltrated with neuroendocrine cells (Figure 2) staining positive for synaptophysin and chromogranin (Figure 3), consistent with metastatic pheochromocytoma. During this time, she was never
Figure 1. Fracture of the sternum at the proximal to mid-aspect with approximately 5 mm of anterior displacement of the distal fragment. There is no gapping. No hematoma or callus formation is present.
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Figure 2. Bone marrow biopsy, left posterior iliac crest: H&E stain showing replacement of the marrow space by nests of cohesive cells with coarse ‘‘salt and pepper’’ chromatin pattern and eosinophilic cytoplasm consistent with metastatic malignant pheochromocytoma.
Figure 3. Diffuse strongly positive chromogranin immunostain confirming neuroendocrine differentiation.
awake enough to communicate, rather she only groaned in discomfort. Her high requirements for narcotics led to increased oxygen requirements, and she was transferred to the intensive care unit. An epidural was placed, through which she received bupivacaine in an attempt to control her pain, but it was still inadequate. She was eventually electively intubated with concern for progressive respiratory depression from the high doses of hydromorphone, fentanyl, and propofol she required. Per request by oncology and her family, she was subsequently extubated for chemotherapy. She
received one round of cytoxan, vincristine, and dacarbazine, but there was no improvement in her pain after chemotherapy. She was started on methadone, haloperidol, gabapentin, and quetiapine in addition to fentanyl and hydromorphone, but she remained delirious and incoherent. Her oxygen requirements continued to increase as she was on bilevel positive pressure ventilation by face mask. Given her intractable pain, the family decided not to have her re-intubated, and she was transitioned to comfort care. She was placed on a morphine drip and died 4 days later. On autopsy, her thyroid was unremarkable. The final report confirmed a 6-cm right adrenal pheochromocytoma with widespread bone metastases, liver metastases, and pleural metastases.
DISCUSSION To establish that pheochromocytoma is malignant, the only definite criterion is the presence of metastases, defined as aberrant endocrine tissue at a site where it is otherwise not found.5 Neuroendocrine cells are typically found in the adrenal medulla, hypothalamus, pituitary gland, and pulmonary epithelium.6 Survival after diagnosis of metastatic disease is highly variable, from months to years.7,8 Common distant sites of malignant pheochromocytoma include bone, liver, lungs, and lymph nodes,7 with the skeletal system being most common. Typical time from diagnosis to discovery of bony metastases is 6.5 years. Bony metastases classically appear as expansile and lytic or sclerotic on imaging.9 This case highlights that the differential for new onset, incapacitating bone pain, along with hypertension and lytic lesions on imaging should include pheochromocytoma. Furthermore, sometimes pain in terminal patients cannot be controlled without compromising respiratory function. The most life-threatening aspect of her case was not catecholamine excess (her blood pressure was well controlled) but unbearable pain from skeletal metastases. Patients may often survive for years with metastatic disease. However, our patient had no further treatment options because pain from her metastatic disease was so functionally limiting that a profound analgesic regimen causing respiratory failure was required to achieve adequate pain control. Ultimately, she died not from hypertensive crisis or other cardiovascular
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complications but because her bone pain was so incapacitating that there was no other way to control her pain while sustaining the quality of life she desired.
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