CASE REPORT
Symptomatic Intraspinal Oncocytic Adrenocortical Adenoma
Jens Schittenhelm . Florian H. Ebner . Patrick Harter . Antje Bornemann
Published online: 28 November 2008 C Humana Press Inc. 2008
Abstract Most intraspinal neoplasms of epithelial origin are metastases from primary carcinomas. Benign epithelial tumors are rarely found at this site. We here present the case of a 44-year-old woman with a lesion in the cauda equina that fulfilled the radiologic criteria of schwannoma and caused clinical symptoms for 3 years. The excised tumor was composed of nests of large polygonal cells with eosinophilic partial granular cytoplasm. Significant atypia, necrosis, and mitosis were absent from this lesion. The tumor showed diffuse positivity for melan-A, synaptophy- sin, and alpha-inhibin. Steroidogenic factor 1 and cytoker- atins 8 and 18 were focally seen in the absence of S-100 and chromogranin. This immunoprofile indicated adreno- cortical origin. Ultrastructural examination showed abun- dant mitochondria, suggesting an oncocytic tumor. The diagnosis of an oncocytic adrenal cortical adenoma was made. These extraadrenal tumors are thought to arise from heterotopic adrenocortical tissue in the spinal cavity. Oncocytic tumors are rare neoplasms and they comprise
J. Schittenhelm ☒ · A. Bornemann
Institute of Brain Research, University Tuebingen, Calwerstr. 3,
72076 Tübingen, Germany e-mail: jens.schittenhelm@med.uni-tuebingen.de
F. H. Ebner Department of Neurosurgery, University of Tübingen, Tübingen, Germany
P. Harter
Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland
P. Harter
Institute of Neurology (Edinger Institute), Johann Wolfgang Goethe University, Frankfurt, Germany
non-functioning variants of adrenal cortical adenomas. To date, only five such intraspinal tumors have been observed. Immunohistochemistry excluded oncocytic paraganglioma, oncocytic meningioma, renal cell carcinoma, alveolar soft part sarcoma, and granular cell tumor. A view of the literature of these rare but probably underdiagnosed intra- spinal tumors is given.
Keywords spinal cord tumor · oncocytic adrenal cortical adenoma · melan-A · synaptophysin · alpha-inhibin
Introduction
Adenomas are benign epithelial neoplasms that are derived from glands. Adrenal cortical adenomas are endocrine in nature and may be functioning or non-functioning [1]. Non- functioning adenomas can go undiagnosed and lesions more than 0.3 cm in greatest dimension have been detected in 3.6% at autopsies of asymptomatic individuals [2]. In patients, “incidentalomas” are detected in increasing numb- ers with high-resolution imaging techniques up to 5% of cases examined [1]. In addition to the adrenal cortex, ectopic tissue has been reported in almost every organ including the central nervous system [3, 4]. Oncocytic neoplasms of adrenal cortical tissue are rare with up to 46 cases reported to date [5]. Similar to oncocytomas of kidney, thyroid, and pituitary, they show no signs of recurrence or metastasis and most of them are hormonally silent [2]. To date, only five intraspinal oncocytomas have been observed. All of them were adrenal cortical adenomas (Table 1).
The presence of an oncocytic adrenal cortical adenoma in the spinal canal was first reported by Kepes et al. [6] in a child and since then to date four more such intraspinal tumors have been reported [7-9]. All intraspinal cases of oncocytic
| Author (year) | Age | Sex | Location | Duration symptoms | Remarks |
|---|---|---|---|---|---|
| Kepes et al. [6] | 8 | F | L2 | 3 weeks | Associated filum terminale lipoma |
| Mitchell et al. [9] | 16 | F | L2 | 3 months | 11-year recurrence-free interval |
| Mitchell et al. [9] | 63 | F | Cauda equina | 10 months | Associated squamous cell carcinoma |
| Kim et al. [19] | 40 | F | Th11-L1 | 1 year | Classified as "Oncocytic paraganglioma" |
| Park et al. [20] | 12 | F | L1 | 6 months | Classified as "oncocytoma of the spinal cord" |
| Cassarino et al. [7] | 27 | M | Conus medullaris | 1 year | |
| Karikari et al. [8] | 27 | F | L2 | 8 weeks | Associated filum terminale lipoma |
| Park et al. [21] | 40 | F | L1-L4 | 3 months | Classified as "oncocytoma of the spinal cord" |
| Current case | 44 | F | L1 | 3 years |
M male, F female
adrenal cortical adenoma reported to date are located in the lumbar region and in two cases were associated with a lipoma. The preoperative diagnosis was myxopapillary ependymoma or schwannoma. All except one case were female and there is no age predilection, spanning the whole spectrum from 8 to 63 years. To confirm the adrenocortical origin of the tumors, radioimmunoassay for androstenedione or enzymatic determination of 3ß-hydroxysteroid dehydro- genase has been employed. Other methods included immu- nostains for adrenal steroidogenic enzymes as P-45011 [beta] hydroxylase, P-450 21 hydroxylase, and P-450-17 alpha hydroxylase [6]. The oncocytic nature of these tumors was confirmed by electron microscopy showing numerous enlarged mitochondria [6, 7].
So far, all of the intraspinal oncocytomas behaved in a benign manner and were cured by gross total resection. There were no reports of tumor recurrence for up to 11 years. We here report another case of an oncocytic benign lesion located in the cauda equina at level L1 which was diagnosed as ectopic adrenocortical adenoma.
Case Report
The 44-year-old female presented with a 3-year history of progressive bilateral leg pain resulting in paresis and reduced
walking ability. There were no bowel or bladder symptoms. Signs of clinical virilization or cushingoid habitus were absent. There was no history of weight loss or spinal cord injuries. Sensibility, coordination, and tendon reflexes were normal. Magnetic resonance imaging of the lumbar spine showed a well-defined right-sided intraspinal mass measuring 2.5 cm in diameter that occupied the spinal canal at L1 level immediately below the medullary conus. This prompted the diagnosis of a schwannoma (Fig. 1). Standard preoperative laboratory evaluation was within normal limits. Microsurgi- cal removal was performed via hemilaminectomy and rendered a brown intradural mass without clear adherence to the nerve roots. A gross total resection was achieved. The postoperative course was uneventful.
Histopathological analysis of the tumor specimen showed large round to polygonal epithelial cells arranged in nests and cords (Fig. 2a). Most nuclei were round and regular, but focally giant hyperchromatic nuclei with inclusions or multinuclear cells were present (Fig. 2b). The cytoplasm of the cells was pale eosinophilic and cells appeared granular (Fig. 2b, arrows). No evidence of atypia, mitotic activity, or necrosis was seen. Periodic acid Schiff (PAS) stain showed very faint positivity of the cytoplasmic granules probably corresponding to lysosomes. Focal sinusoidal dilatation of the capillary lumina was seen (Fig. 2b), but cytoplasmic vacuolization or stromal tissue
H
L 1
a
b
C
a
HE
b
HE
C
CK8
d
CK18
e
Melan-A
f
Synaptophysin
g
a-Inhibin
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SF-1
was absent. While immunostaining for pan-cytokeratin (clone MNF116) and keratins (AE1/AE3), cytokeratins 7 and 20 were negative; some tumor cells showed strong perimembranous expression of cytokeratin 8 (Fig. 2c) and to a lesser extent cytokeratin 18 (Fig. 2d) suggesting epithelial origin of the tumor cells. Additional stains demonstrated strong cytoplasmic positivity in most tumor cells for melan-A (MART-1, Fig. 2e), synaptophysin
(Fig. 2f), and alpha-inhibin (Fig. 2g). In contrast, the tumor was negative for S-100, glial-fibrillary acidic protein, neuron-specific enolase (NSE), chromogranin A, epithelial membrane antigen, thyroid transcription factor 1, thyro- globulin, smooth muscle actin, CD117 (c-KIT), and human melanoma black (HMB-45). Expression of vimentin was restricted to vessels and interstitial connective tissue cells. The proliferation index for Ki67 (MiB-1) was 3% and the
number of p53-expressing nuclei was similar. In addition, the nuclei stained positive for steroidogenic factor 1 (Ad4BP/SF-1, Fig. 2h) which is involved in adrenal steroidogenesis. Electron microscopy revealed abundant mitochondria in the tumor cells (Fig. 3) and confirmed the oncocytic nature of the tumor.
Taken together, this was a benign oncocytic tumor that showed the immunoprofile of an adrenal cortical adenoma; hence, the diagnosis of an oncocytic adrenocortical adeno- ma was made. The lack of mitotic activity and invasion as well as the clinical history ruled out the possibility of an adrenocortical carcinoma. In addition, follow-up magnetic resonance imagings of the adrenal gland showed no tumor.
Discussion
The tumor described here fulfilled all diagnostic criteria for a benign oncocytic adrenal cortical neoplasm. Positive expression of steroidogenic factor 1 [10], melan-A [11], alpha-inhibin [12], neuron-specific enolase [13], and synap- tophysin [13] has been previously used to diagnose cortical adenomas. Coupled with negative immunostaining for chromogranin, S-100, and HMB-45, this ascertained the diagnosis [5, 13]. Histologic criteria indicative of malignancy (defined as major criteria according to Lin. et al.) consisting of more than five mitoses in 50 high-power fields, atypical mitoses, or venous invasion and uncertain malignant potential (minor criteria) such as large tumor size, necrosis, and capsular or sinusoidal invasion were absent [13]. The definitional criteria for a oncocytic adrenocortical adenomas consisting of eosinophilic (granular) cytoplasm, high nuclear grade, and diffuse growth were met [13].
The origin of intraspinal adrenal tumors is not clear. It is assumed that they are derived from ectopic adrenocortical tissue. These are “adrenal rests” and may be found along the embryonic migration path in spermatic cord, adnexa of testes, groin, and retroperitoneal space [14, 15]. The most common site for adrenal ectopic tumors is the kidney. Clinical symptoms in the current case were directly attributed to compression of spinal structures, again distinguishing the neoplastic lesion in the current case from adrenal rest.
Oncocytic tumors include paraganglioma, meningioma, alveolar soft part sarcoma, granular cell tumor, and carcinoma. Our case lacked the typical features of para- ganglioma, i.e., “zellballen architektur,” chromogranin expression, and S-100-positive sustentacular cells. Onco- cytic meningiomas express epithelial membrane antigen and usually show typical meningothelial features [16]. Alveolar soft part sarcomas reveal intracellular PAS- positive crystalline material and varying amounts of glycogen. These may occasionally express S-100 and NSE but lack the synaptophysin expression seen in our cortical adenoma. In addition, variable muscle marker expression is seen in more than 50% of the alveolar soft part sarcomas [17]. Our case did not show expression of markers for any myogenic differentiation. In addition, oncocytic renal cell carcinoma was ruled out due to the bland histology and lack of immunoreactivity for cytoker- atin 7, CD10, or vimentin. Negative immunostaining of S- 100 and lack of PAS-positive inclusions also ruled out granular cell tumor. Finally, there is an unusual case report of the oncocytic variant of an intraspinal melanocytoma displaying melanin pigment deposits and immunopositivity of S-100 and HMB-45 that our case lacked [18].
Cassarino et al. [7] noted another two oncocytic neo- plasms within the lumbar region, one of which was classified as oncocytic paraganglioma but does not herald evidence of sustentacular cells or S-100 expression [19, 20]. A search of the literature reveals another case recently published [21]. In all cases, it might be possible that these tumors are adrenal cortical adenomas. Moran and colleagues [22] examined 30 spinal paragangliomas and noted eosinophilic granular cells in two cases “suggestive of oncocytic metaplasia” but did not go into detail whether they were devoid of chromogranin and S-100. In another case of an oncocytic paraganglioma showing focal cytokeratin expression, the authors speculated “that they are derived from (misplaced) endoderm, rather than from visceral-autonomic paraganglia” but since they also report immunopositivity of S-100 protein this case remains enigmatic [23].
Previous cases of adrenal cortical adenomas were mainly ascertained by enzyme histochemistry. The present case demonstrates the usefulness of an immunohistochemistry panel (synaptophysin, melan-A, S-100, GFAP, chromogra- nin, CK18) in paraffin-embedded material together with
electron microscopy to establish the proper diagnosis. Inhibin and melan-A staining has been employed only in the two most recent studies and showed positivity for both markers [7, 8], while all tumors shown in Table 1 were negative for GFAP, S-100. These were also negative for chromogranin A, except for the initial study that did not use a chromogranin antibody [6]. Almost all studies reporting the tumors to be negative for cytokeratins have employed keratin cocktails. These results need to be interpreted with caution as shown in the current case which was also negative for AE1/AE3 but demonstrated strong immunore- activity for low-level keratins CK8 and CK18 which are consistently seen in oncocytic adrenal neoplasms [13]. Results on vimentin and NSE are mixed; some cases have been reported as positive others as negative without further going into detail which types of cells have been stained [6- 9, 13]. In agreement with the description of Mitchell and colleagues [9], we report that expression of vimentin is restricted to delicate interstitial connective tissues and vessels but not in tumor cells.
Taken together, intraspinal oncocytic adrenal cortical adenoma are non-functioning and mimic the clinical and radiographic features of schwannomas. Gross total resec- tion appears to be curative. Use of an immunostaining panel consisting of alpha-inhibin, synaptophysin, melan-A, S- 100, chromogranin, CK18, and SF-1 allows for establishing the proper diagnosis.
Acknowledgement We like to thank Prof. Stephan Störkel, Institute of Pathology, Helios Kliniken Wuppertal and Prof. Falko Fend, Institute of Pathology, University Tübingen for helpful discussions and Katrin Trautmann for technical help.
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