Case Challenges

A 54-year-old woman with bilateral hydronephrosis

A 54-year-old black woman presented to her primary care physician after experiencing worsening fatigue and abdominal pain for about 1 month.

A CT scan of her abdomen showed pelvic lymphadenopathy. She was scheduled for an outpatient biopsy but, in the interim, she developed increasing swelling in her legs, prompting a visit to the ED.

The patient’s medical history was significant for hypertension, diabetes, hyperlipidemia and deep venous thrombosis. Medications included hydrochlorothiazide, lisinopril, metoprolol (Lopressor, Novartis), pravastatin (Pravachol, Bristol-Myers Squibb), glipizide (Glucotrol, Pfizer) and metformin. A review of symptoms was significant for weight loss, loss of appetite, nausea, leg swelling and abdominal pain.

Ramya Varadarajan, MD

Ramya Varadarajan

Lab workup showed a white blood cell count of 15.8, hemoglobin of 7.1 g/dL, a platelet count of 726,000 cells/mL, sodium level of 128, potassium of 8.3 mmol/L, blood urea nitrogen of 95 mg/dL, creatinine of 7.8 gm/dL, lactate dehydrogenase of 4,338 IU/L and ferritin of 758 ng/mL. Liver function tests were normal, and hepatitis and HIV tests were negative.

Repeat CT of the abdomen and pelvis showed confluent retroperitoneal adenopathy — which previously measured 10 cm x 6 cm — now measured 12 cm x 8 cm. This completely encased the aorta and inferior vena cava, extending to the renal hilum, resulting in moderate hydronephrosis.

The adenopathy extended inferiorly into the pelvis, particularly in the left pelvic wall. The lobulated pelvic wall lymph node, which previously measured 10 cm x 4 cm, now measured 12 cm x 5 cm. The uterus was enlarged with multiple fibroids and was displaced to the right by the pelvic adenopathy.

Diffuse soft tissue anasarca was noted involving both lower extremities, likely due to venous compression from the adenopathy. ECG showed peaked T waves with widened QRS complexes.

She underwent emergent dialysis, with improvement of her hyperkalemia. She had bilateral percutaneous nephrostomy tubes placed by interventional radiology for her hydronephrosis. This was complicated by bleeding, and her hemoglobin dropped from 7.1 g/dL to 4.6 g/dL.

She received three units of packed red blood cells and her hemoglobin level improved. Her renal failure slowly recovered after her nephrostomy tubes were placed, and she was able to come off dialysis within the next few days. She had a staging workup, including CT of the chest and brain. Chest CT showed left supraclavicular and right posterior mediastinal adenopathy. Several other nodes were seen near the epicardium and in the right internal jugular region. CT of the head was negative for metastatic disease. She failed to improve clinically, even after her renal function recovered. She had severe anorexia and resulting malnutrition, which required parenteral nutrition.

She underwent CT-guided biopsy of her pelvic lymphadenopathy. Fine-needle aspiration biopsy of the retroperitoneal mass revealed a malignant neoplasm with hyperchromatic pleomorphic cells with nuclear molding and necrosis. The cells were negative for pancytokeratin, CD19 and CD45.

The case was forwarded to Mayo Clinic for a second opinion. The diagnosis of neuroendocrine neoplasm, most suggestive of neuroblastoma, was rendered. Immunohistochemistry revealed that the neoplastic cells are positive for synaptophysin, chromogranin and CD56. They were negative for CD99, smooth muscle actin (SMA), desmin, cytokeratin CAM 5.2, cytokeratin OSCAR, melan-A and inhibin.

After detailed discussion of the pathology, staging and prognosis, the patient and family decided to proceed with palliative care.

Disease characteristics

Neuroblastoma is an embryonal neural crest tumor that involves the peripheral sympathetic nervous system. It can arise anywhere in the sympathetic nervous system. The adrenal gland is the most common primary site (40%), followed by abdominal (25%), thoracic (15%), cervical (5%) and pelvic sympathetic ganglia (5%). Neuroblastoma metastasizes to lymph nodes, bone marrow, cortical bone, dura, orbits, liver and skin. Less frequently, it metastasizes to pulmonary and intracranial sites.

It is a rare malignancy. Approximately 500 cases are diagnosed each year in the United States. Approximately 90% of cases develop in children younger than 10 years.

It has a broad spectrum of clinical behavior, which can range from spontaneous regression or a benign ganglioneuroma to aggressive disease with metastatic dissemination. The presenting symptoms reflect the location of the primary tumor and the extent of metastatic disease, if present.

Neuroblastoma tumor cells are characterized by defective catecholamine synthesis, which results in the accumulation and excretion of the intermediates homovanillic acid (HVA), vanillylmandelic acid (VMA) and dopamine. Secretion of these catecholamines may give rise to symptoms (eg, hypertension). In addition, HVA and VMA can be measured in the urine and are useful for diagnosis and in monitoring disease.

Most patients will undergo laboratory evaluations, including routine blood counts, serum chemistries, and tests of liver and kidney function. Evaluation of urine or serum catecholamine metabolite levels, VMA and HVA should be obtained to assist in diagnosis and monitoring of disease response because levels are elevated in more than 90% of patients with neuroblastoma. In addition, ferritin and lactate dehydrogenase concentrations may be helpful; they may be elevated initially and can be expected to return to normal during adequate treatment.

Imaging modalities such as ultrasound, CT, MRI and bone scan are used as part of staging workup. Metaiodobenzylguanidine (MIBG) is a chemical analog of norepinephrine that is selectively concentrated in sympathetic nervous tissues such as neuroblastoma. It can be labeled with radioactive iodine and imaged by scintigraphy. The MIBG scan is both sensitive and specific for neuroblastoma, and it is recommended at diagnosis and repeat evaluations of the tumor. Histologic confirmation is required for definitive diagnosis. Tissue usually is obtained by incisional biopsy of the primary tumor or bone marrow biopsy/aspirate in patients who are suspected to have metastatic disease in the marrow.

Diagnosis and treatment

Neuroblastoma may be diagnosed by morphology, as a monotonous collection of small, round, blue cells similar to that of other small round blue cell tumors. Neuroblastomas typically react with antibodies that distinguish neural tissue (eg, neuron-specific enolase [NSE], synaptophysin, chromogranin and S100). Although NSE may be positive in other tumors (eg, rhabdomyosarcoma), the staining pattern is characteristically diffuse and strongly positive in neuroblastomas. Deletions of chromosome 1p are associated with amplification of the MYCN oncogene. They are found in approximately 25% of neuroblastomas and are an indicator of poor prognosis.

Minimum criteria for establishing a diagnosis of neuroblastoma have been agreed upon by an international consensus panel.

A definitive diagnosis of neuroblastoma requires either one of the following:

  • Histologic diagnosis from tumor tissue by light microscopy, with or without immunohistochemistry, electron microscopy, or increased urine or serum catecholamines.
  • Evidence of metastases to bone marrow on an aspirate or biopsy with concomitant elevation of urinary or serum catecholamines or their metabolites.

Factors that influence the clinical behavior of neuroblastomas include tumor stage, age at diagnosis, pathologic risk classification, cytogenetics and molecular genetics. These factors have been combined to define low-, intermediate- and high-risk groups, which are used to define treatment strategies.

Treatment options for adults are based on pediatric studies. Because of the rarity of the disease in adults, no prospective studies are available. Surgery is the mainstay of treatment for low-risk tumors, although some may need additional chemotherapy. In intermediate-risk disease, a combined-modality approach that includes chemotherapy and surgical resection is standard. In high-risk neuroblastoma, substantial improvements in long-term outcomes have been seen with aggressive combined-modality approaches. These generally include chemotherapy, surgical resection, high-dose chemotherapy with stem cell rescue, radiation therapy and biologic/immunologic therapy.

In conclusion, although neuroblastoma is rare in adults, it is important to consider in the differential diagnosis of small round blue cell tumors. Adult neuroblastomas have distinct biologic features, including low frequency of MYCN amplification, urine catecholamine elevation and MIBG avidity. Multiple studies have shown prognosis of neuroblastoma worsens with age.

References:

Esiashvili N. Pediatr Blood Cancer. 2007;49:41-46.

Smith L. Ann Clin Lab Sci. 2013;43:81-84.

For more information:

Ramya Varadarajan, MD, is a consultant at Regional Hematology and Oncology, PA, at Helen Graham Cancer Center in Newark, Del. She can be reached at Regional Hematology & Oncology, 4701 Ogletown Stanton Road, Suite 2400, Newark, DE 19713.

Disclosure: Varadarajan reports no relevant financial disclosures.

A 54-year-old black woman presented to her primary care physician after experiencing worsening fatigue and abdominal pain for about 1 month.

A CT scan of her abdomen showed pelvic lymphadenopathy. She was scheduled for an outpatient biopsy but, in the interim, she developed increasing swelling in her legs, prompting a visit to the ED.

The patient’s medical history was significant for hypertension, diabetes, hyperlipidemia and deep venous thrombosis. Medications included hydrochlorothiazide, lisinopril, metoprolol (Lopressor, Novartis), pravastatin (Pravachol, Bristol-Myers Squibb), glipizide (Glucotrol, Pfizer) and metformin. A review of symptoms was significant for weight loss, loss of appetite, nausea, leg swelling and abdominal pain.

Ramya Varadarajan, MD

Ramya Varadarajan

Lab workup showed a white blood cell count of 15.8, hemoglobin of 7.1 g/dL, a platelet count of 726,000 cells/mL, sodium level of 128, potassium of 8.3 mmol/L, blood urea nitrogen of 95 mg/dL, creatinine of 7.8 gm/dL, lactate dehydrogenase of 4,338 IU/L and ferritin of 758 ng/mL. Liver function tests were normal, and hepatitis and HIV tests were negative.

Repeat CT of the abdomen and pelvis showed confluent retroperitoneal adenopathy — which previously measured 10 cm x 6 cm — now measured 12 cm x 8 cm. This completely encased the aorta and inferior vena cava, extending to the renal hilum, resulting in moderate hydronephrosis.

The adenopathy extended inferiorly into the pelvis, particularly in the left pelvic wall. The lobulated pelvic wall lymph node, which previously measured 10 cm x 4 cm, now measured 12 cm x 5 cm. The uterus was enlarged with multiple fibroids and was displaced to the right by the pelvic adenopathy.

Diffuse soft tissue anasarca was noted involving both lower extremities, likely due to venous compression from the adenopathy. ECG showed peaked T waves with widened QRS complexes.

She underwent emergent dialysis, with improvement of her hyperkalemia. She had bilateral percutaneous nephrostomy tubes placed by interventional radiology for her hydronephrosis. This was complicated by bleeding, and her hemoglobin dropped from 7.1 g/dL to 4.6 g/dL.

She received three units of packed red blood cells and her hemoglobin level improved. Her renal failure slowly recovered after her nephrostomy tubes were placed, and she was able to come off dialysis within the next few days. She had a staging workup, including CT of the chest and brain. Chest CT showed left supraclavicular and right posterior mediastinal adenopathy. Several other nodes were seen near the epicardium and in the right internal jugular region. CT of the head was negative for metastatic disease. She failed to improve clinically, even after her renal function recovered. She had severe anorexia and resulting malnutrition, which required parenteral nutrition.

She underwent CT-guided biopsy of her pelvic lymphadenopathy. Fine-needle aspiration biopsy of the retroperitoneal mass revealed a malignant neoplasm with hyperchromatic pleomorphic cells with nuclear molding and necrosis. The cells were negative for pancytokeratin, CD19 and CD45.

The case was forwarded to Mayo Clinic for a second opinion. The diagnosis of neuroendocrine neoplasm, most suggestive of neuroblastoma, was rendered. Immunohistochemistry revealed that the neoplastic cells are positive for synaptophysin, chromogranin and CD56. They were negative for CD99, smooth muscle actin (SMA), desmin, cytokeratin CAM 5.2, cytokeratin OSCAR, melan-A and inhibin.

After detailed discussion of the pathology, staging and prognosis, the patient and family decided to proceed with palliative care.

Disease characteristics

Neuroblastoma is an embryonal neural crest tumor that involves the peripheral sympathetic nervous system. It can arise anywhere in the sympathetic nervous system. The adrenal gland is the most common primary site (40%), followed by abdominal (25%), thoracic (15%), cervical (5%) and pelvic sympathetic ganglia (5%). Neuroblastoma metastasizes to lymph nodes, bone marrow, cortical bone, dura, orbits, liver and skin. Less frequently, it metastasizes to pulmonary and intracranial sites.

It is a rare malignancy. Approximately 500 cases are diagnosed each year in the United States. Approximately 90% of cases develop in children younger than 10 years.

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It has a broad spectrum of clinical behavior, which can range from spontaneous regression or a benign ganglioneuroma to aggressive disease with metastatic dissemination. The presenting symptoms reflect the location of the primary tumor and the extent of metastatic disease, if present.

Neuroblastoma tumor cells are characterized by defective catecholamine synthesis, which results in the accumulation and excretion of the intermediates homovanillic acid (HVA), vanillylmandelic acid (VMA) and dopamine. Secretion of these catecholamines may give rise to symptoms (eg, hypertension). In addition, HVA and VMA can be measured in the urine and are useful for diagnosis and in monitoring disease.

Most patients will undergo laboratory evaluations, including routine blood counts, serum chemistries, and tests of liver and kidney function. Evaluation of urine or serum catecholamine metabolite levels, VMA and HVA should be obtained to assist in diagnosis and monitoring of disease response because levels are elevated in more than 90% of patients with neuroblastoma. In addition, ferritin and lactate dehydrogenase concentrations may be helpful; they may be elevated initially and can be expected to return to normal during adequate treatment.

Imaging modalities such as ultrasound, CT, MRI and bone scan are used as part of staging workup. Metaiodobenzylguanidine (MIBG) is a chemical analog of norepinephrine that is selectively concentrated in sympathetic nervous tissues such as neuroblastoma. It can be labeled with radioactive iodine and imaged by scintigraphy. The MIBG scan is both sensitive and specific for neuroblastoma, and it is recommended at diagnosis and repeat evaluations of the tumor. Histologic confirmation is required for definitive diagnosis. Tissue usually is obtained by incisional biopsy of the primary tumor or bone marrow biopsy/aspirate in patients who are suspected to have metastatic disease in the marrow.

Diagnosis and treatment

Neuroblastoma may be diagnosed by morphology, as a monotonous collection of small, round, blue cells similar to that of other small round blue cell tumors. Neuroblastomas typically react with antibodies that distinguish neural tissue (eg, neuron-specific enolase [NSE], synaptophysin, chromogranin and S100). Although NSE may be positive in other tumors (eg, rhabdomyosarcoma), the staining pattern is characteristically diffuse and strongly positive in neuroblastomas. Deletions of chromosome 1p are associated with amplification of the MYCN oncogene. They are found in approximately 25% of neuroblastomas and are an indicator of poor prognosis.

Minimum criteria for establishing a diagnosis of neuroblastoma have been agreed upon by an international consensus panel.

A definitive diagnosis of neuroblastoma requires either one of the following:

  • Histologic diagnosis from tumor tissue by light microscopy, with or without immunohistochemistry, electron microscopy, or increased urine or serum catecholamines.
  • Evidence of metastases to bone marrow on an aspirate or biopsy with concomitant elevation of urinary or serum catecholamines or their metabolites.

Factors that influence the clinical behavior of neuroblastomas include tumor stage, age at diagnosis, pathologic risk classification, cytogenetics and molecular genetics. These factors have been combined to define low-, intermediate- and high-risk groups, which are used to define treatment strategies.

Treatment options for adults are based on pediatric studies. Because of the rarity of the disease in adults, no prospective studies are available. Surgery is the mainstay of treatment for low-risk tumors, although some may need additional chemotherapy. In intermediate-risk disease, a combined-modality approach that includes chemotherapy and surgical resection is standard. In high-risk neuroblastoma, substantial improvements in long-term outcomes have been seen with aggressive combined-modality approaches. These generally include chemotherapy, surgical resection, high-dose chemotherapy with stem cell rescue, radiation therapy and biologic/immunologic therapy.

In conclusion, although neuroblastoma is rare in adults, it is important to consider in the differential diagnosis of small round blue cell tumors. Adult neuroblastomas have distinct biologic features, including low frequency of MYCN amplification, urine catecholamine elevation and MIBG avidity. Multiple studies have shown prognosis of neuroblastoma worsens with age.

References:

Esiashvili N. Pediatr Blood Cancer. 2007;49:41-46.

Smith L. Ann Clin Lab Sci. 2013;43:81-84.

For more information:

Ramya Varadarajan, MD, is a consultant at Regional Hematology and Oncology, PA, at Helen Graham Cancer Center in Newark, Del. She can be reached at Regional Hematology & Oncology, 4701 Ogletown Stanton Road, Suite 2400, Newark, DE 19713.

Disclosure: Varadarajan reports no relevant financial disclosures.