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A 57-year-old man presented with a history of low back pain for the past 6 months. Imaging revealed cauda equina mass. A single fragment of red-tan soft tissue measuring 3.7 x 2.1 x 1.0 cm was received. Serial sectioning revealed a pink-tan surface with two areas of hemorrhage.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 11 and is a Paraganglioma of the cauda equina.
Criteria for Diagnosis and Comments:
Sections show a highly vascular, well-encapsulated mass with hyalinized blood vessels. Tumor cells are bland and show low nuclear-to-cytoplasmic ratios. Mitoses are not evident. In many areas, the tumor cells manifest long tapering cell processes oriented perpendicularly toward blood vessels, simulating ependymoma. However, in other foci, a more nested, zellballen appearance is seen. The diagnosis of paraganglioma is confirmed by the presence of positive immunostaining for chromogranin and synaptophysin in the chief cells, as well as for S100 and GFAP in the sustentacular cells. Immunostaining is negative for S100, EMA and GFAP within the main cell type within the tumor, the chief cells. A MIB-1 cell cycle labeling index is usually less than 5%.
The differential diagnosis in this cauda equina/filum terminale location includes schwannoma, metastatic tumors, meningioma, and ependymoma, particularly those of the myxopapillary type. In examples of paragangliomas, such as this one, where the clusters of tumor cells form more noticeable nests or “zellballen”, these other considerations are more readily excluded. However, in paragangliomas of the cauda equina, other growth patterns besides the zellballen pattern may predominate. Paragangliomas are diagnostically most challenging when the chief cells of the tumor orient around blood vessels, forming perivascular pseudorosette-like structures and simulating a cellular ependymoma. Attention to the fact that it is the elongated, tubular cytoplasm that is tapering down towards the blood vessel in a paraganglioma, rather than wispy, fibrillary cell processes as in an ependymoma, helps clarify the diagnosis even on H&E light microscopy. Other uncommon patterns for paragangliomas may include ribbon-like formation (adenomatous pattern), spindle shaped cells, and oncocytic change within the tumor cells. Cases with these patterns may be less readily recognized as paragangliomas without adjuvant immunostaining.
If paraganglioma is included in the pathologist’s differential diagnostic list for cauda equina tumors, the finding of immunoreactivity for neuron specific enolase (NSE) (seen in 100% of examples) or synaptophysin (at least 91% of examples) completely clarifies that the tumor is paraganglioma, not myxopapillary ependymoma. Some authors have reported very focal GFAP staining in the sustentacular cells. In contrast, myxopapillary ependymoma would be expected to show strong GFAP immunoreactivity, particularly in the fibrillary cell processes of the perivascular tumor cells forming pseudorosettes. In addition, myxopapillary ependymoma generally contains a prominent mucoid matrix that accumulates around tumor cells and especially around blood vessels, producing Alcian-blue-positive, mucin-filled microcysts. Both myxopapillary ependymoma and paraganglioma of the cauda equina have lower nuclear-to-cytoplasmic ratios and lower mitotic rates and MIB-1 cell cycle labeling indices, compared to metastatic tumors. Schwannomas are strongly and diffusely S100 positive in both nucleus and cytoplasm and often contain a rich parallel reticulin network within the dense Antoni A areas of the tumor. Depending on the antibody utilized, schwannomas may also show focal GFAP immunoreactivity, but it is not in the strong and perivascular pattern seen in myxopapillary ependymomas, nor is it within sustentacular-like cells.
In occasional cases, electron microscopy (EM) may be necessary to establish the diagnosis. The most characteristic, and constant feature, is the presence of dense core neurosecretory granules, averaging 150 nm in diameter within the type I (chief cells) of a paraganglioma. Some filaments of intermediate type, 8-10 nm diameter, can be seen in the cytoplasm as well. The finding of dense core granules excludes myxopapillary ependymoma, schwannoma, meningioma, and most metastatic carcinomas from consideration. The possible overlap with metastatic melanoma is usually further rectified by recognizing the nested pattern, the accompanying type II sustentacular cells, and the more bland indolent features for a paraganglioma compared to melanoma.
Several additional features of paragangliomas of the cauda equina can cause confusion for the pathologist. The first is that these tumors have a significant propensity to manifest ganglionic differentiation. This feature is not commonly seen with paragangliomas at other sites, although it can occasionally be seen with a related tumor, pheochromocytoma. Another source of confusion is the fact that the intermediate filaments referred to above that can reside within the cytoplasm of chief cells may show immunoreactivity for cytokeratins. In the study by Moran et al., focal keratin positivity was seen in 21% of cases.
Further possible source of confusion is if the differential diagnosis by the pathologist does not include paraganglioma at all but focuses on the other diseases listed above. In situations where the pathologist is assuming the diagnosis is myxopapillary ependymoma, a large percentage of paragangliomas will show immunoreactivity for S100 protein (95%) or GFAP (30%), again in the sustentacular cells. If the pathologist is not cognizant of the typical GFAP immunoreactive pattern for myxopapillary ependymomas, this immunostaining can be misinterpreted.
Paragangliomas of the cauda equina most commonly occur in middle-aged adults. The range is 12 to 71 years with a mean of 48 years. There is a slight male predominance of 1.5 to 1. Low back pain is almost always of one year’s duration, or more, by the time the diagnosis is made. As expected, low back pain would be shorter in more malignant conditions. Ninety percent of patients present with low back pain and 72% of these patients have sciatica. Sensory or motor deficits are identified in 35%, urinary/fecal incontinence in 13%, and paraplegia in 6%. An unusual presentation of increased intracranial pressure due to malabsorption of cerebrospinal fluid has also rarely been reported in patients with paraganglioma of the cauda equina.
Paragangliomas occur sporadically and are unassociated with inherited tumor syndromes. Almost all are hormonally inactive. Immunostaining for hormones such as adrenocorticotrophic hormone (ACTH) is very rare.
These are slow growing tumors which can usually be cured by gross total surgical resection. Although exceptional cases with metastases have been described, it should be remembered that local recurrence may represent inadequate surgical resection and not malignancy. Paragangliomas of the cauda equina are Grade I tumors according to the WHO classification system.