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Diffuse Cytokeratin Positivity in an Intradural Paraganglioma of the Lumbar Vertebra: A Diagnostic Pitfall!

To the Editor: Paragangliomas arise from the paraganglia, a diffuse network of neuroendocrine tissues of common embryological origin. The 2 classical categories are the sympathetic type and parasympathetic type. The majority of the sympathetic type are adrenal (pheochromocytomas), and the majority of the parasympathetic type are located within the head and neck (chemodectomas, glomus tympanicum, etc.).1 Numerous other locations for paragangliomas have been reported, including: periaortic, pelvic, and within the conus medullaris.2 Paragangliomas are rare; the incidence of pheochromocytomas ranges from 0.4 to 9.5/1,000,000 and the surgical incidence of head and neck paragangliomas is thought to be <1/1,000,000.3 The prototypic histology consists of whorled clusters of neoplastic chief cells (“Zellballen” architecture) with surrounding sustentacular cells and intervening loose fibrovascular septae. The lesional cells are typically positive for general neuroendocrine markers including: chromogranin A, synaptophysin, and CD56.1 S-100 staining will often nicely outline sustentacular cells,1 and cytokeratin staining is usually negative. We report herein, a case of a 60year-old gentleman with a 40-year history of chronic lower back pain with extension to the legs. He also complained of acute and transient episodes of leg weakness and painful paresthesias of the legs and thighs. Magnetic resonance imaging demonstrated a discrete and enhancing lesion at the tip of the conus medullaris at the L1 level. The underlying bone and musculature did not demonstrate any abnormalities, and the clinical diagnosis was thought to be schwannoma. An L1-L2 laminectomy revealed a 1.2-cm tan-white, rubbery, and encapsulated intradural tumor encircling a nerve root of the conus medullaris. Both the nerve root and tumor were resected. Histology showed a well circumscribed thinly encapsulated nodule composed monotypic round to oval cells with eosinophilic cytoplasm and central nuclei with fine chromatin disposed in a nested array by delicate fibrovascular septae. Hemorrhagic areas as well as central infarction are present. By immunohistochemistry, the cells are positive for synaptophysin and chromogranin, S-100 and negative for CK7, CK20, CDX-2, and TTF-1. Noteworthy, the S-100 staining was diffuse, highlighting both nested tumor cells and the sustentacular cell network, although the stain was darker in the sustentacular cells. The Ki-67 proliferative index was low at approximately 0.1% to 0.2%. Surprisingly, the tumor cells were also diffusely and strongly positive for pancytokeratin (AE1/3), which raised the question of possible metastatic neuroendocrine carcinoma. However, the overall longstanding clinical history, histomorphology, immunophenotypic expression, and pattern of S-100 reactivity were considered supportive of paraganglioma despite the aberrant cytokeratin expression. Cytokeratin expression has been reported in paragangliomas in the past, albeit rarely. Usually, this expression can be found in cauda equina paragangliomas and is weak and/or focal. In a study by Chetty and colleagues, 18 cases of extra-adrenal paraganglioma and 7 cases of adrenal paraganglioma/ pheochromocytoma were stained with CAM 5.2 and AE1/AE3.4 Although all pheochromocytomas were negative for both cytokeratin immunostains, 3 cases of extra-adrenal paraganglioma showed diffuse and intense staining for CAM 5.2, and 2 of these 3 cases showed diffuse and intense staining for AE1/AE3. The cases were from the cauda equina, the orbit, and intravagal, with the cauda equina tumor showing weaker AE1/AE3 staining.