JBJS | Symptomatic Ganglioneuroma of Bone. A Case Report*

The Journal of Bone & Joint Surgery, Volume 81, Issue 11

Articles | November 01, 1999

Symptomatic Ganglioneuroma of Bone. A Case Report*

KAI MITHÖFER, M.D.†; ERIC F. GRABOWSKI, M.D., SC.D.†; ANDREW E. ROSENBERG, M.D.†; DANIEL P. RYAN, M.D.†; HENRY J. MANKIN, M.D.†, BOSTON, MASSACHUSETTS

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Investigation performed at Massachusetts General Hospital and Harvard Medical School, Boston

The Journal of Bone & Joint Surgery. 1999; 81:1589-95

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Introduction

Introduction | Case Report | Discussion | References

Ganglioneuromas are uncommon benign tumors that are thought to be derived from the nonchromaffin cells of the sympathetic nervous system. Primary ganglioneuromas usually arise from sympathetic elements located between the craniovertebral junction and the pelvis. These lesions tend to grow slowly, typically are dumbbell-shaped, and may cause progressive compression of spinal nerve roots or erosion into adjacent osseous structures^10,19,22,26. Primary soft-tissue ganglioneuroma with secondary erosion into bone should be differentiated from ganglioneuroma that has metastasized to bone. The latter phenomenon is the result of skeletal metastasis of neuroblastoma with subsequent spontaneous maturation of this highly malignant tumor to ganglioneuroma. To the best of our knowledge, only two cases of ganglioneuroma of bone developing from spontaneous differentiation of metastatic neuroblastoma have been reported in the literature^9,32. We describe a case of disseminated ganglioneuroma of the skeleton that presented with an impending pathological fracture and that closely mimicked the clinical findings of polyostotic fibrous dysplasia.

*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

†Departments of Orthopaedic Surgery (K. M. and H. J. M.), Pediatrics (E. F. G.), Pathology (A. E. R.), and Pediatric Surgery (D. P. R.), Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail address for Dr. Mankin: hmankin@partners.org.

*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

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Fig. 1 Plain radiographs of the right humerus (A), the right and left tibiae (B and C), and the right and left femora (D and E), made on February 2, 1998. The radiographs show osteolytic and slightly expansile ganglioneuromatous lesions of the metaphyseal and diaphyseal regions of these tubular bones. The lesions appear hazy, with internal trabeculation and mild cortical thinning. Bowing of both tibial shafts is noted.

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Fig. 2 Photomicrograph of a specimen of tissue from the left femur, obtained with intraoperative curettage, made on February 7, 1998. The image demonstrates bone trabeculae surrounded by an abundant fibrillary background (hematoxylin and eosin, x 64) containing predominantly well differentiated spindle cells and dispersed mature ganglion cells (arrow and inset) (hematoxylin and eosin, x 160).

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Fig. 3 Computed tomographic scan of the abdomen, made on February 25, 1998, demonstrating a well defined mass, with low attenuation and multiple calcifications (arrows) without enhancement by contrast medium, in the right supra-adrenal region.

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Fig. 4 T1-weighted spin-echo sagittal magnetic resonance image of the thoracolumbar spine, made on February 26, 1998, revealing ganglioneuromatous vertebral lesions (arrow) with moderate signal intensity (repetition time, 550 milliseconds; echo time, eleven milliseconds).

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Fig. 5 Technetium-99m scintiscans made on February 26, 1998, demonstrating moderately increased radionuclide uptake in the left femur and a mild increase in the right femur and both tibiae. Faint signal was noted in the distal aspect of the right humerus. Areas of increased uptake are associated with the location of the lesions as demonstrated on plain radiographs.

Case Report

Introduction | Case Report | Discussion | References

A seventeen-year-old girl was referred to the Orthopaedic Oncology Service at Massachusetts General Hospital because of progressively increasing pain of fourteen months' duration in the left thigh. The pain, which initially had been mild, was aggravated by weight-bearing and interfered with sleep. The patient had been diagnosed as having polyostotic fibrous dysplasia two years earlier, after she sustained a pathological fracture of the right tibia, which was treated nonoperatively. Radiographs made at that time had demonstrated well defined radiolucent lesions in the tibial shafts and the proximal aspects of the femora, and there had been slightly increased radionuclide uptake and low signal intensity on T1-weighted magnetic resonance images and high signal intensity on T2-weighted images. The medical history also included a traumatic fracture of the distal aspect of the right radius and a reconstruction of the auditory canal with residual hypoacusis at the age of five years for what had been reported by the parents as a cyst.

The findings on physical examination included localized tenderness in the midportion of the left thigh without a palpable deformity, mass, or inguinal adenopathy. There were no other abnormalities other than several café-au-lait spots on the trunk. Laboratory studies revealed normal findings except for an erythrocyte sedimentation rate of thirty-nine millimeters per hour (normal, a maximum of seventeen millimeters per hour). The complete blood-cell count, results of liver-function tests, and levels of calcium, phosphorus, alkaline phosphatase, sugar, blood urea nitrogen, and creatinine were all within normal limits. A skeletal survey demonstrated lesions in the central aspect of the diaphysis and in the metaphysis of the right femur, the central aspect of the diaphysis of both tibiae, and the distal aspect of the right humerus (Fig. 1, A and D). Plain radiographs of the left femur demonstrated an expansile, osteolytic lesion in the diaphysis with focally sclerotic margins. There was a septated appearance with internal trabeculation and a ground-glass appearance (Fig. 1, E). The lesions in the other bones had a similar radiographic appearance. No associated soft-tissue changes were observed.

The patient's history and the radiographic and clinical appearance of the left femur indicated an impending pathological fracture; thus, elective closed fixation with an intramedullary rod was performed. Frozen sections of intraoperative specimens obtained by curettage from the proximal femoral lesion demonstrated ganglioneuroma (Fig. 2); this finding was confirmed on analysis of the permanent sections, with positive immunohistochemical staining for S-100 protein and neurofilament.

The pathological diagnosis suggested that the skeletal lesions represented metastases of a previously unrecognized stage-IV neuroblastoma³ or ganglioneuroblastoma with spontaneous maturation. Subsequent computed tomographic scans of the chest, abdomen, and pelvis suggested that a partially calcified right adrenal mass, measuring 7.0 by 7.4 centimeters, was the likely primary tumor (Fig. 3). There was no evidence of involvement of other abdominal or pelvic organs; however, a number of well defined lytic lesions of the ribs and vertebrae were identified. Magnetic resonance imaging of the abdomen showed no communication of the right adrenal mass with the neural foramina or the spinal canal.

Vertebral lesions of the caudad part of the thoracic spine and the cephalad part of the lumbar spine demonstrated low-to-moderate signal intensity on T1-weighted images (Fig. 4) and moderate-to-high signal intensity on T2-weighted spin-echo images. Technetium-99m methylene diphosphonate scintigraphy revealed increased activity in the proximal aspect of the left femur, mild uptake in the right femur and both tibiae, and faint signal in the right humerus (Fig. 5). Additional laboratory studies showed normal levels of urine vanillylmandelic acid (2.9 milligrams per twenty-four hours; normal, zero to 3.9 milligrams per twenty-four hours) and homovanillic acid (6.8 milligrams per twenty-four hours; normal, 1.4 to 7.2 milligrams per twenty-four hours).

The patient had a right thoracoabdominal adrenalectomy and lymph-node sampling as well as bilateral biopsy of the bone marrow of the posterior iliac crest. The entire adrenal mass and the lymph nodes were examined histologically with light and electron microscopy. The diagnosis was ganglioneuroma without evidence of neuroblastoma or ganglioneuroblastoma (Fig. 2). Flow-cytometric DNA and cell-cycle analysis demonstrated diploidy (DNA index, 1), with 85 percent G₀G₁, 6 percent S-phase, and 9 percent G₂M; all of these values are within the range for most benign conditions². No amplification of the N-myc oncogene was detected in tissue samples with use of fluorescent in situ hybridization. The bone-marrow biopsy showed normocellular bone marrow with normal trilineage maturation, and cytogenetic analysis revealed a 46,XX karyotype.

The patient tolerated the procedure well and had an uneventful recovery. Postoperatively, an iodine-123 meta-iodobenzyl-guanidine scan showed no evidence of uptake at the sites of known disease. Retrospective analysis of the records of the previous procedure on the right ear revealed that the patient had had a modified radical mastoidectomy and tympanoplasty for the histological diagnosis of ganglioneuroma.

Three months postoperatively, the patient reported a two-week history of severe back pain. Plain radiographs showed lesions of the vertebral bodies and pedicles, loss of height of most of the thoracic vertebrae, and compression of the eleventh thoracic and second lumbar vertebral bodies, all of which were treated nonoperatively.

Discussion

Introduction | Case Report | Discussion | References

Ganglioneuromas are rare tumors that are derived from the sympathetic nervous system, and they represent only a small fraction of all soft-tissue tumors¹⁹. To our knowledge, polyostotic ganglioneuroma has been described in only two case reports to date^9,32. In a comprehensive review of 243 cases of ganglioneuroma, it was concluded that the differentiated tumor does not metastasize²⁷. According to current theory, diffuse ganglioneuroma is the result of spontaneous maturation of metastasis from neuroblastoma or ganglioneuroblastoma, the most common extracranial solid malignant tumor in children. Metastatic neuroblastoma frequently involves bone and is associated with a low rate of survival^6,20. Spontaneous cytomaturation is seen in a very small number of stage-IV neuroblastomas, and that finding is associated with an increased rate of survival^5,7,25. However, according to the International Neuroblastoma Staging System, this stage-IV-S neuroblastoma is characterized by a distinct metastatic pattern that excludes osseous metastasis³. Skeletal metastasis from neuroblastoma is almost invariably associated with a fatal outcome³⁰. Thus, the present case of diffuse osseous spread of neuroblastoma with spontaneous cytomaturation of both the primary tumor and osseous metastatic deposits is a pathological rarity that, to the best of our knowledge, has been described in only two previous cases^9,32.

The case of our patient is interesting from an orthopaedic standpoint insofar as medical attention was sought because of skeletal symptoms. Long-standing localized bone pain was also the only symptom in the other adult patient with polyostotic ganglioneuroma who is described in the literature³². In contrast, diarrhea resulting from paraneoplastic production of vasoactive intestinal peptide prompted medical consultation to be sought in the case involving a child⁹. Osseous involvement by metastatic ganglioneuroma appears to be polyostotic, with a predilection for the long bones and the spine; these sites were predominantly involved in all three reported cases. The finding of the lesions in these locations supports the hypothesis that the ganglioneuromatous skeletal lesions originated from metastasizing neuroblastoma, as skeletal metastases in neuroblastoma show a predilection for similar regions of the long bones¹. Symmetrical lesions were observed in the long bones of the lower extremities of our patient but not in those of the patients who were reported on previously. Ganglioneuroma of the pelvis, ribs, and skull was identified only once in the literature. Interestingly, our patient had a history of cochlear ganglioneuroma, an entity that has been reported in only one patient previously¹⁸.

Histological differentiation of neuroblastoma to ganglioneuroma with osseous metastasis has been documented following chemotherapy and radiation therapy in two additional patients^10,25. In those patients, the mandible, skull, humerus, femora, ribs, spine, and pelvis were affected. However, Garvin et al.⁹ clearly distinguished treatment-associated maturation from spontaneous differentiation since the former is not associated with an improved outcome. Therefore, cases involving treatment-associated maturation must be interpreted separately from those involving spontaneous maturation.

Polyostotic fibrous dysplasia, which was the presumptive clinical diagnosis in our patient, represents an important differential diagnosis of polyostotic ganglioneuroma. The primary findings of pain in the lower extremity with impending fracture; metaphyseal and diaphyseal involvement and focal cortical thinning of the tubular bones with irregularly defined, hazy radiolucency; internal trabeculation; and a zone of reactive sclerosis closely mimic the presentation of polyostotic fibrous dysplasia¹¹. Ganglioneuromatous involvement of the ribs, as observed in our patient, also suggests fibrous dysplasia, as this is the most frequent benign lesion of the rib cage⁸. On magnetic resonance imaging, the signal characteristics of ganglioneuroma are similar to those of fibrous dysplasia; both lesions show low signal intensity on T1-weighted images and intermediate or high signal intensity on T2-weighted images⁸. Normal levels of alkaline phosphatase, found in two-thirds of patients who have fibrous dysplasia¹⁴, are also compatible with this diagnosis. Abnormal cutaneous pigmentation with café-au-lait spots, which our patient had, is found on examination of one-half of patients who have polyostotic fibrous dysplasia⁸. Owing to the more severe manifestations of polyostotic fibrous dysplasia, affected patients are, as a group, considerably younger than those who have monostotic disease and ganglioneuroma; two-thirds of patients with polyostotic fibrous dysplasia are seen before the age of ten years⁸.

In contrast to ganglioneuroma, polyostotic fibrous dysplasia frequently involves the skull, the facial bones, and the shoulder girdle and infrequently involves the spine⁸. Spinal involvement was present in all three reported cases of skeletal ganglioneuroma. Bone scans of patients who have fibrous dysplasia characteristically show increased activity owing to the intrinsic hypervascularity of the lesions. Computed tomography demonstrates lesions with greater density (seventy to 130 Hounsfield units) because of the increased density of primitive bone trabeculae in fibrous dysplasia^8,16,28. Finally, histological analysis of polyostotic fibrous dysplasia demonstrates thin, curved trabeculae of woven bone surrounded by fibrous tissue. No ganglion cells are present, and immunohistochemical analysis is negative for S-100 and neurofilament.

Radiographically, the osseous lesions caused by ganglioneuroma are seen as benign-appearing radiolucent areas with defined, focally sclerotic margins and without associated soft-tissue changes. There may be focal cortical thinning, and this may account for the osseous symptoms. As was seen in our patient, pathological fracture may occur in the long bones while vertebral collapse may result from spinal involvement⁹. The ground-glass appearance of the ganglioneuromatous skeletal lesions, as observed in our patient, is probably the result of an internally trabeculated and loculated configuration with focal ossification of the matrix. Abundant lobulations and focal calcifications, also typical features of primary ganglioneuroma¹⁹, were present in the adrenal primary tumor in our patient.

The plain radiographic skeletal survey as well as the technetium-99m bone scan demonstrated faint increased uptake in the region of the lesions in the long bones and a moderate reactive increase at the site of the impending fracture and of the operative intervention. The lesions were not detectable with use of technetium scintigraphy in one of the previously reported cases⁹, and this diagnostic modality was not available for the other³². This pattern of enhancement of the ganglioneuromatous bone lesions on conventional bone scans indicates that the osteoblastic activity or vascularity of the lesions, or both, are equal to or only slightly greater than those in the normal surrounding bone¹, suggesting that these lesions are relatively inactive. This theory is supported by the long asymptomatic course in our patient and in that of the other patient³² who had skeletal symptoms during early adulthood.

No focal uptake was detected with use of iodine-123 meta-iodobenzyl-guanidine scintigraphy in our patient. This agent is more sensitive for detecting disseminated osseous involvement by neuroblastoma because, unlike the bone-seeking agents used in conventional bone scans, it is not taken up in normal bone. However, because false-negative iodine-123 meta-iodobenzyl-guanidine scans have been described in association with more differentiated components of neuroblastoma¹³, technetium-99m methylene diphosphonate scintigraphy always should be used to supplement this technique for the diagnosis of ganglioneuroma of bone^1,4,13. Nevertheless, the negative result for our patient suggests the absence of neuroblastoma tissue in the diffuse skeletal lesions.

The characteristic radiographic features of primary ganglioneuroma include low-to-intermediate attenuation (less than forty Hounsfield units) with punctate calcifications on computed tomography and high signal intensity on T2-weighted magnetic resonance images, with lack of enhancement on early dynamic studies performed with gadolinium¹⁷. The case of our patient demonstrates the characteristics of skeletal ganglioneuroma on magnetic resonance imaging and computed tomography, which appear to be similar to the features observed in primary tumors. Both of these modalities are useful for screening for the primary tumor, which is mandatory when ganglioneuroma of bone has been identified because primary osseous ganglioneuroma does not occur. In our patient, such screening led to the discovery of a large supra-adrenal mass. An adrenal primary tumor also was demonstrated in the other patient who had osseous metastasis⁹, while limited radiographic modalities did not identify the primary tumor in the third patient³².

Normal levels of alkaline phosphatase and a mild-to-moderate increase in the erythrocyte sedimentation rate were found in our patient and in one of the patients reported on previously³². Although these findings indicate low osseous turnover, these parameters are nonspecific and must be interpreted with caution. The levels of vanillylmandelic and homovanillic acid in the urine should be measured, since elevated levels are found in most patients who have neuroblastoma, as a result of a deficit of phenylethanolamine-N-methyltransferase. The absence of vanillylmandelic and homovanillic acid in the urine from our patient indicated the differentiated state and benign nature of the tumor.

Because of the rarity of this tumor and its nonspecific radiographic and clinical presentation, the correct diagnosis was not made for our patient until the findings of histopathological analysis were available. Histological analysis of ganglioneuroma demonstrates mature ganglion cells dispersed among neurofibrillary stroma, with well formed neurites and fusiform and mature-appearing Schwann cells¹⁵. Mature gangliocytic differentiation is characterized by large ganglion cells with a low nucleus-to-cytoplasm ratio. Electron microscopy reveals well developed rough endoplasmic reticulum systems, frequent lysosomes, residual bodies, and myelin figures¹⁵. Typically, mature ganglion cells are associated with satellite cells that are immunoreactive to S-100 antibodies¹⁵. Positive staining of satellite cells for S-100 protein also was observed in specimens from our patient. Immunohistochemical reactivity to neurofilament is another useful marker, as strong staining is seen with ganglioneuroma whereas undifferentiated neuroblastoma shows little reactivity³³. Importantly, the histological analysis must be very thorough because the tumors may be composed of both mature ganglioneuroma and undifferentiated neuroblastoma, as classically described for composite ganglioneuroblastoma²⁷. Investigation of the N-myc proto-oncogene is mandatory in the workup for ganglioneuroma of bone. Amplification of N-myc is observed frequently in poorly differentiated neuroblastic tumors, and its level of expression appears to decrease with increasing differentiation³¹. The lack of N-myc expression in our patient further supports the diagnosis of benign ganglioneuroma. Complete staging also includes bone-marrow biopsy to rule out marrow dissemination, a finding that was not present in our patient.

Because of the differentiation, maturity, and slow-growing behavior of skeletal ganglioneuroma, there is no role for radiation or chemotherapy in its treatment¹². The indications for treatment include incapacitating pain, progressive deformity that jeopardizes the integrity of the axial skeleton or is cosmetically disfiguring, and impending pathological fracture. Coxa vara, shepherd's crook deformity, and major deviation of the spinal axis should be prevented. Expendable bones such as the clavicle, fibula, and ribs are easy to resect if they are symptomatic. Early curettage and bone-grafting is recommended for progressive coxa vara. Operative stabilization helps to maintain the alignment and length of the long bones. Since thinned cortices do not allow stable screw or plate fixation, intramedullary fixation is preferred, although it may be technically difficult if osseous deformity is present. Arthrodesis and instrumentation may be necessary for the treatment of severe angular deformities of the vertebrae²³. Identification and resection of the primary tumor is mandatory in order to uncover any remaining malignant residuals such as are found in composite-type ganglioneuroma or neuroblastoma.

The potential for malignant conversion of skeletal ganglioneuroma is not known. However, occasional development of malignant nerve-sheath tumors from ganglioneuroma has been reported²¹. Lack of N-myc expression and strong immunohistochemical detection of S-100 and neurofilament indicate a differentiated state and are positive prognostic indicators^9,24,31. The long asymptomatic period between the diagnosis of cochlear ganglioneuroma in our patient at the age of five years and the osseous symptoms at the age of fifteen years also supports the prognosis of a benign tumor. As mature ganglion cells have no tendency for proliferation⁹, the expansile nature of the ganglioneuromatous osseous lesions probably is the result of the slow growth of the abundant schwannian stroma of osseous ganglioneuroma. The same mechanism by which primary ganglioneuroma erodes adjacent osseous structures from the outside may cause cortical thinning of bone from within by intraosseous ganglioneuroma. Symptoms and fracture appear to be caused primarily by lesions affecting the weight-bearing axial skeleton, where cortical thinning becomes symptomatic and leads to functional limitation earlier in the course of the disease.

In summary, osseous ganglioneuroma, although rare, should be considered in the differential diagnosis of polyostotic benign skeletal lesions, particularly fibrous dysplasia²⁹. Because of its clinical similarity with fibrous dysplasia, biopsy is required for accurate diagnosis. If the findings on histological study are positive, screening for a primary tumor is imperative. Molecular and immunohistochemical markers should be used to confirm the benign nature of the neoplasm. Treatment is indicated for progressive deformity or pathological fracture, observed most often in the axial skeleton. Because of the limited experience with this disease and its unknown long-term prognosis, close observation is warranted.

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