A 20-year-old, previously healthy, white male, presented with low back and right flank pain for 2 weeks. The pain was varying in intensity from moderate to severe and diffuse and radiating to the groin, with no exacerbating or relieving factors and minimal relief with ibuprofen. He said the pain started after he was in a high velocity motor vehicle accident. According to the patient, his car was hit from behind by another vehicle, which resulted in skidding and the patient’s car landing upside down. There was no loss of consciousness. The patient was evaluated by the emergency medical system after the accident and was discharged after a computerized tomography (CT) scan of the head failed to show any evidence of injury or bleed. The laboratory investigations done at that time revealed low hemoglobin.
Further questioning revealed that the patient had been constipated for 1 month and had multiple episodes of flushing, usually coinciding with the increase in pain severity. His past history was significant for bipolar disorder, depression, and attention-deficit/hyperactivity disorder (ADHD). He had been taking divalproex sodium for 3 months. He admitted non-compliance with medication. He had been hospitalized numerous times for psychiatric issues. The last hospitalization was 1 year ago for suicidal ideation.
On physical examination, he was a well-appearing male with blood pressure of 172/94, heart rate of 92 bpm, respiratory rate of 14 bpm, and temperature of 100.8°F. There was tenderness and slight fullness in the right lower quadrant. There were a few 1- to 2-cm, enlarged anterior cervical lymph nodes. The patient had small, itchy, painful, red nodules, up to 1 cm, which were widely spread over his face, neck, back, and abdomen, with some degree of mucositis. The rest of the physical exam, including the neurological exam, was non-contributory.
For diagnosis, see page 611.
Over the next few days, the patient had a wide variability of blood pressure, ranging from 190/94 mm Hg to 134/60 mm Hg. The laboratory investigations performed at that time were significant for hemoglobin of 9.5 g/dL; a total white count of 5.95 k/uL with 63% neutrophils; 26% lymphocytes; and a platelet count of 329 k/uL. The blood cultures drawn when the patient was febrile were negative. Liver function tests were done and were within normal range. Serum phosphorus was slightly elevated at 5.6 mg/dL. A CT scan of the abdomen revealed a large, right adrenal mass with a large calcified component and multiple scattered lucencies throughout the spine and pelvis.
As conventional treatment for pain control failed to show any improvement, the patient was admitted and started on a hydromorphone PCA pump. Magnetic resonance imaging (MRI) of the spine revealed diffuse bone marrow irregularities, with moderate to severe right neural foraminal narrowing at the level of T9-10 and T11-12. A CT-guided biopsy of the right adrenal mass and a bone marrow biopsy were performed, which revealed the diagnosis.
The CT-guided biopsy from the right adrenal mass was reported as neuroblastoma with poor stroma, some differentiation, low mitotic karyorrhexis index (MKI), and an unfavorable histology. Following this, a bone marrow biopsy was performed, which revealed diffuse involvement of the bone marrow with small, round blue cells.
Although neuroblastoma is the most common solid extra-cranial neoplasm of children, it is rarely reported in adults, with fewer than 10% of cases occurring after 10 years.1
Neuroblastoma is a tumor arising from the embryonal cells of the sympathetic nervous system. The signs and symptoms of the disease may vary, depending on the site of the primary tumor. Bone pain due to metastasis to the bones and the marrow is a common presentation. Sometimes, patients have neurological deficits because of the compression of the spinal cord by bony metastasis. Some patients may also present with generalized malaise, fatigue, fever, and other constitutional symptoms.
Some specific symptoms associated with neuroblastoma, although not exhibited by our patient, are periorbital ecchymosis, also known as raccoon eyes, due to infiltration of the periorbital tissue by the tumor cells, and intractable diarrhea, due to secretion of vasoactive intestinal peptide by the tumor cells.
This is more common in younger age groups; nearly two-thirds of patients with neuroblastoma have abdominal primaries.2 Approximately 2% of patients present with opsoclonus myoclonus, a paraneoplastic syndrome characterized by the presence of myoclonic jerks and dancing eyes. In infants, neuroblastoma may manifest as bluish lumps under the skin, also known as blueberry muffin syndrome. About 92% of the cases have hypertension as the only presenting symptom.2
Most cases are diagnosed by biopsy from the primary site. Other tests, including urine and plasma homovanillic acid (HVA), vanillylmandelic acid (VMA), and Nmyc gene amplification tests, can be performed to support the diagnosis. Although HVA is a metabolite of dopamine, VMA is a metabolite of norepinephrine. Their levels are increased in all tumors, which secrete catecholamines. Most review of the literature supports that it is rare for adults with neuroblastoma to exhibit increased excretion of HVA and VMA or the Nmyc amplification.3
Our patient presented with acute posttraumatic back pain, with no constitutive signs or symptoms. His occupational history and the severity of the motor vehicular crash were highly suggestive of a traumatic etiology. Unresponsiveness of the pain to routine pain medications made muscle sprain less likely. Because there were no neurological deficits, spinal cord injury was disregarded. After the physical exam revealed fullness in the right lower quadrant, CT scan of the abdomen was performed.
The findings of the CT suggested bony metastasis with an adrenal tumor. At this, we broadened our differentials to include neuroblastoma, malignant pheochromocytoma, paraganglioma, lymphoma, leukemia, and teratoma. Considering that the adrenal gland is the fourth most common site of metastasis, it was also possible that the adrenal mass and the bone lucencies were metastasis from a distant primary tumor, such as from the lungs, skin, thyroid, and colon.
Pheochromocytoma, neuroblastoma, and ganglioneuroma were high on our differentials (see Table). Besides the adrenal mass and bony metastasis, a high variability in blood pressure and paroxysmal episodes of flushing supported our diagnosis.
Table. Comparisons Among Neuroblastoma and Pheochromocytoma and Ganglioneuroma
In our patient, urine HVA and VMA levels were done, which showed very high levels of 31.6 mg/g creatinine (normal range 1.4 to 5.3) and 83.1 mg/g creatinine (normal range 1.1 to 4.1), respectively.
According to the pathology report of the adrenal mass biopsy and the bone marrow findings, our patient had International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma. Because of the rarity of the cases occurring in the adult population, there is no standardized therapy for adults, and most adults are treated based upon the pediatric chemotherapy protocol. Myeloablative therapy has been reported to be beneficial for children with neuroblastoma in their first remission; however, its utility in older patients with neuroblastoma has not yet been established.
He received cycle 1 of chemotherapy with topetecan, vincristine, and cyclophosphamide, which he tolerated well. The skin lesions disappeared after treatment with topical bacitracin. Despite a low MKI, this patient had a poor prognosis because of his age at presentation and because the disease was in stage 4 with poor differentiating stroma. The patient was lost to follow-up.
Although rare in children older than 10 years, neuroblastoma should be considered as the differential diagnosis of any patient presenting with an abdominal mass or bone metastasis. Appropriate diagnosis should be established using a biopsy from the tumor site.
- Esiashvili N, Goodman M, Ward K, Marcus RB, Johnstone PA. Neuroblastoma in adults: incidence and survival analysis based on SEER data. Pediatr Blood Cancer. 2007;49(1):41–46. doi:10.1002/pbc.20859 [CrossRef]
- Brouwers FM, Eisenhofer G, Lenders JW, Pacak K. Emergencies caused by pheochromocytoma, neuroblastoma, or ganglioneuroma. Endocrinol Metab Clin North Am. 2006;35(4):699–724. doi:10.1016/j.ecl.2006.09.014 [CrossRef]
- Kushner BH, O’Reilly RJ, LaQuaglia M, et al. Dose intensive use of cyclophosphamide in ablation of neuroblastoma. Cancer. 1990;66(6):1095–1100. doi:10.1002/1097-0142(19900915)66:6<1095::AID-CNCR2820660603>3.0.CO;2-0 [CrossRef]
- Boyle JG, Davidson DF, Perry CG, Connell JM. Comparison of diagnostic accuracy of urinary free metanephrines, vanillyl mandelic acid, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma. J Endocrinol Metab. 2007;92(12);4602–4608. doi:10.1210/jc.2005-2668 [CrossRef]
- Brossard J, Burnstein ML, Lemieux B. Neuroblastoma: an enigmatic disease. Br Med Bull. 1996;52(4):787–801.
- Castleberry RP. Biology and treatment of neuroblastoma. Pediatr Clin North Am. 1997;44(4):919–937. doi:10.1016/S0031-3955(05)70537-X [CrossRef]
- Haase GM, Perez C, Atkinson JB. Current aspects of biology, risk assessment and treatment of neuroblastoma. Semin Surg Oncol. 1999;16(2):91–104. doi:10.1002/(SICI)1098-2388(199903)16:2<91::AID-SSU3>3.0.CO;2-1 [CrossRef]
- Stowens D. Neuroblastoma and related tumors. AMA Arch Pathol. 1957;63(5):451–453.
- Radin R, David CL, Goldfarb H, et al. Adrenal and extra-adrenal retroperitoneal ganglioneuroma: imaging findings in 13 adults. Radiology. 1997;202(3):703–707.
- Carpenter WB, Kernohan JW. Retroperitoneal ganglioneuromas and neurofibromas: a clinicopathological study. Cancer. 1963;16:788–797. doi:10.1002/1097-0142(196306)16:6<788::AID-CNCR2820160615>3.0.CO;2-Z [CrossRef]
Each month, this department features a discussion of an unusual diagnosis in genetics, radiology, or dermatology. A description and images are presented, followed by the diagnosis and an explanation of how the diagnosis was determined. As always, your comments are welcome via e-mail at email@example.com.
Figure 1. CT Scan of the Abdomen Revealed a Large, Right Adrenal Mass with a Large Calcified Component and Multiple Scattered Lucencies Throughout the Spine and Pelvis.
Comparisons Among Neuroblastoma and Pheochromocytoma and Ganglioneuroma
|Age at diagnosis||< 10 years mostly1||30–40 years2||Mean 7 years|
|Presentation||Abdominal mass2||Paroxysmal hypertension2||Mass effect, 50% asymptomatic8–10|
|Most common primary site||65% abdomen, chest, pelvis, and neck5–7||Adrenal medulla 50%2||Posterior mediastinum 38%, retroperitoneum8–10|
|Most common site of metastasis||Lymph nodes, bone, and bone marrow2||Lymphatics, lungs, liver, bone2||Lymphatics|
|Percentage that metastasizes||50%7||10%2||< 1%|
|Urinary HVA, VMA, metanephrines||92% increase in HVA and VMA2||Metanephrines more specific4||20% to 39%2|