The Oncologist, Vol. 13, No. 2, 152-156, February 2008; doi:10.1634/theoncologist.2006-0180
© 2008 AlphaMed Press
Case Report: An Unusual Case of Adrenal Neuroblastoma in Pregnancy
Marwan M. Refaata,
Shereene Z. Idrissb,
Lawrence S. Blaszkowskya,c
aDepartment of Medicine,
bDepartment of Dermatology, and
cDivision of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
Key Words. Adrenal • Adult • Neuroblastoma • Pregnancy
Correspondence: Correspondence: Marwan Refaat, M.D., Massachusetts General Hospital, Department of Medicine, GRB 740, 55 Fruit Street, Boston, Massachusetts 02114, USA. Telephone 617-726-2862; Fax: 617-724-7441; e-mail: rifaatmarwan{at}hotmail.com
Received October 30, 2006;
accepted for publication December 23, 2007.
Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.
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ABSTRACT
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Neuroblastomas are the fourth most common malignancy of childhood and account for most adrenal tumors in children. However, they are rarely reported in adults. We present herein an extremely rare case of adrenal neuroblastoma occurring in a 25-year-old woman during her first trimester of pregnancy. She had a spontaneous abortion secondary to chorioamnionitis and she was operated on for an "incidentaloma." Her tumor was curatively resected. She presented with right lower quadrant abdominal pain 26 months after her operation and there was evidence of local tumor recurrence without metastasis. Adult adrenal neuroblastoma is an uncommon malignancy and, to our knowledge, there was no case of this tumor occurring in pregnancy ever described in the English literature. The case presentation is followed by a general discussion with an emphasis on the diagnosis, treatment, and follow-up of neuroblastoma and its association with pregnancy.
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CASE PRESENTATION
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A 25-year-old woman was in her usual state of health until she presented in her 10th week of pregnancy complaining of abdominal cramping and vaginal bleeding. She had a spontaneous abortion as a result of chorioamnionitis. Physical exam revealed a nontender palpable firm mass in her right lower abdomen.
As part of the evaluation, a transvaginal ultrasound was performed, revealing a 14 x 10 cm mass adjacent to the right adrenal gland. Magnetic resonance imaging (MRI) of the mass without contrast confirmed a heterogeneous right adrenal mass (Fig. 1). Urine levels of vannilyl mandelic acid (VMA), dopamine, total metanephrines, and normetanephrine were all elevated, at 28.4 mg (reference range, <8 mg), 553 µg (age-adjusted female range, 65–400 µg), 637 µg (age-adjusted female range, 190–583 µg), and 477 µg (age-adjusted female range, 103–390 µg), respectively, in 24 hours. Because of the biochemical compatibility, the "incidentaloma" was initially diagnosed as a pheochromocytoma.
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Figure 1. Magnetic resonance imaging scan of the mass without contrast confirmed an 11.1 x 10.4 x 11.6 cm heterogeneous right adrenal mass with areas of hemorrhage, high signal on T1-weighted images, and no fat saturation.
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During right adrenalectomy, a rounded mass measuring 11.5 cm was found near the right lobe of the liver and originating in the right adrenal gland. Surrounded by residual adrenal gland tissue, the mass was excised, and the examined resection margins were negative for tumor (Fig. 2). Direct extra-adrenal extension was not identified. Areas of cystification and necrosis were noted within the mass. No complications were encountered during the postoperative period, and the 24-hour urine catecholamines were within the normal range.
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Figure 2. The macroscopic appearance of the adrenal mass showed an 11.5 x 11 x 5 cm tan-red adrenal mass with a smooth to focally irregular surface. Sectioning revealed a tan to red, multiloculated, solid, and cystic internal surface and focal areas of hemorrhage.
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A histopathological examination revealed a tumor with undifferentiated primitive-appearing round blue cells in a lobular pattern, forming sheets of Homer-Wright rosettes suggestive of a neuroblastoma. No ganglion cells were seen. A low mitosis karyorrhexis index (MKI) (<100/5000 tumor cells) and unfavorable age-adjusted Shimada histology were characteristic findings consistent with an undifferentiated stroma-poor neuroblastoma (Fig. 3). On immunohistochemical stains, the tumor cells were positive for chromogranin and synaptophysin, and negative for melan A, S-100, and cytokeratin. The immunophenotype further supported the diagnosis of neuroblastoma. Fluorescence in situ hybridization for 1p36 deletion was negative and no N-myc amplification was detected, all of which suggested a more favorable prognosis.
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Figure 3. The microscopic appearance of the specimen showed a tumor with undifferentiated, primitive-appearing, round blue cells in a lobular pattern, forming sheets of Homer-Wright rosettes. (Hematoxylin and eosin stain, magnification 125x.)
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Based on imaging, surgical, and pathology findings, the patient's International Neuroblastoma Staging System (INSS) stage is stage I. The staging workup included a positron emission tomography (PET) scan, repeat computed tomography (CT) scan of the chest, abdomen, and pelvis, bone scan, and bilateral bone marrow aspirates and biopsies, all of which revealed no evidence of metastatic disease.
The patient was doing well on a follow-up 20 months after her surgery. Her 24-hour urine collection was remarkable for a VMA level of 6.4 mg (reference range, < 8 mg), metanephrine level of 79 µg (age-adjusted female range, 30–180 µg), normetanephrine level of 247 µg (age-adjusted female range, 103–390 µg), and total metanephrine level of 326 µg (age-adjusted female range, 142–510 µg). The plan was to observe the patient with CT scans every 6 months until 5 years after her adrenelectomy. Unfortunately, she was noncompliant with her imaging studies despite multiple notifications. She presented back 26 months after her surgery with right lower abdominal pain for which a CT scan of the abdomen and pelvis was performed. This demonstrated a mass appearing to arise from the right adrenal gland remnants measuring 5.3 x 3.9 cm exerting a mass effect on the inferior vena cava anteriorly and right kidney medially, and displacing the kidney laterally. The findings are likely suggestive of recurrence of the neuroblastoma. A PET scan showed faint, heterogeneous radiotracer uptake with a more intense focus superiorly in the region of the adrenalectomy bed corresponding to a soft tissue mass seen on a recent CT. A chest CT showed no evidence of metastatic disease to the chest. She underwent surgical resection of the tumor, which was an 8-cm right retroperitoneal stroma-poor undifferentiated neuroblastoma. The resected margins were negative for malignancy. The patient had a normal bone marrow biopsy and aspirate.
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CLINICAL PRESENTATION AND WORKUP
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Neuroblastoma refers to a malignancy derived from primitive neural crest cells of the adrenal medulla. Neuroblastomas are the fourth most common malignancy of childhood [1]. Up until September 2007, no more than 60 neuroblastomas in adults had been reported in the literature. The most common manifestations are to the result of a tumor mass, most likely an abdominal mass, or bone pain from metastases. A large percentage of neuroblastomas undergo spontaneous regression, and this could possibly account for the scarcity of its presence among the adult population [2]. Typically presenting at 22 months, they display no predilection for gender [3]. Clinical data suggest that >40% of neuroblastomas arise from within the adrenal gland. Symptoms associated with the diagnosis are usually unrelated to any catecholamine imbalance. However, on rare occasions, compression of the renal artery may lead to hypertension as a presenting manifestation [4]. The most common symptoms are a hard, asymptomatic mass in the abdomen, or bone pain resulting from metastatic spread.
Neoplasms are extremely uncommon in pregnancy, although malignancies of the breast, cervix, and ovaries have been well documented throughout the obstetric literature. Hormonal changes associated with pregnancy, especially in the late phase of the third trimester, when estrogen levels reach a maximum, have been known to play a role in the amplification of tumor growth. It has been suggested that estrogen may play a role in the development of soft tissue sarcomas.
Although a biopsy is considered the sine qua non of diagnosing a neuroblastoma, laboratory studies and imaging play essential roles as part of the evaluation. Twenty-four-hour urine catecholamine levels and their metabolites such as VMA are often elevated, and may lead to an initial diagnosis of pheochromocytoma.
A plain abdominal radiograph, including the kidneys, ureters, and bladder, is also recommended in the primary assessment. After the identification of a mass on x-ray, a renal/bladder sonogram should be performed. This noninvasive imaging modality allows for a more thorough diagnostic evaluation. The laterality of the mass, its size, and the presence of calcifications are observed by abdominal CT. MRI may provide information regarding invasion into regional lymph nodes and vessels. Bone scintigraphy and/or a skeletal survey are often helpful when bone metastasis is suspected [1].
The histopathological examination of neuroblastoma reveals a tumor with undifferentiated, primitive-appearing round blue cells with hyperchromatic nuclei and scant cytoplasm in a lobular pattern. Sheets of Homer-Wright pseudorosettes, consisting of neuroblasts surrounding eosinophilic neuropil, are a pathognomonic feature confirming the diagnosis of neuroblastoma [5–7].
Shimada et al. [8] developed a classification scheme for neuroblastomas. The system uses the degree of neuroblast differentiation, the Schwannian stromal quality, the MKI, the growth pattern, and the patient's age to classify the histology as either favorable or unfavorable. Patients belonging to one of the three following categories are considered within the favorable category:
- Patients of any age with stroma-rich tumors without a nodular pattern.
- Patients <18 months old with stroma-poor tumors, an MKI <200/5,000 (200 karyorrhectic cells per 5,000 cells scanned), and differentiated or undifferentiated neuroblasts.
- Patients <60 months old with stroma-poor tumors, an MKI <100/5,000, and well-differentiated tumor cells.
Staging, along with age at diagnosis and certain tests on tumor specimens, such as histology and N-myc amplification, play critical roles in the recommendations of specific treatment modalities [9]. The INSS is shown in Table 1.
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TREATMENT
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Although neuroblastoma is among the curable tumors in young children, it is associated with a worse prognosis in adults, with a 5-year median survival rate after diagnosis <40% [10–12]. Patients are classified into one of three risk groups: low, intermediate, and high risk. A combination of factors, consisting of the International Neuroblastoma Classification scheme along with tumor biology such as N-myc amplification, tumor stage including metastases and ploidy, and patient age, help define the three risk categories described above.
Studies have demonstrated that, for low-risk patient groups (patients with low-stage neuroblastoma such as stage 1, 2A, or 2B) like our patient, total surgical excision is curative >95% of the time. Several factors, such as tumor location, especially regarding its relationship to major nerves and blood vessels, the presence of metastases, patient age, and tumor mobility, determine the resectability of the tumor. For patients in whom resectability of the tumor may compromise vital organs, surgery should be postponed until after combination chemotherapy has been administered to reduce the size of the tumor. The success of such an approach has been demonstrated by several studies [13–15]. Chemotherapy is reserved for patients with favorably localized yet unresectable disease, or who present with life-threatening symptoms such as spinal cord compression. A commonly used drug combination of low- or moderate-intensity chemotherapy is often used, and includes active agents such as cyclophosphamide, doxorubicin, carboplatin, and etoposide [16–24].
Although the prognosis of this disease is poor in adults, our patient had a favorable low-risk assessment of her tumor [25]. She had stage 1 disease with a local recurrence completely excised, and her tumor lacked N-myc amplification. Urine studies (VMA, metanephrine, normetanephrine, dopamine) and a CT scan of the chest, abdomen, and pelvis will be repeated in 6 months.
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ACKNOWLEDGMENTS
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Marwan Refaat and Shereene Idriss contributed equally to the article.
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FOOTNOTES
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Conception/design: Marwan M. Refaat, Shereene Z. Idriss, Lawrence S. Blaszkowsky
Data analysis and interpretation: Marwan M. Refaat, Shereene Z. Idriss, Lawrence S. Blaszkowsky
Manuscript writing: Marwan M. Refaat, Shereene Z. Idriss, Lawrence S. Blaszkowsky
Final approval of manuscript: Marwan M. Refaat, Lawrence S. Blaszkowsky
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Abstract
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