Calcifying pseudoneoplasm of the neuraxis (CAPNON) associated with neurenteric cyst: an autopsy case showing unusual fatal outcome

Background Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare calcied tumefactive lesion that can occur in the brain or spine. Although the aetiology and natural course of CAPNON has not yet been fully established, recent study reported that many CAPNON cases have dual pathology, which may be associated with its aetiology. A 53-year-old man with a history of an untreated brain mass was taken to a hospital by emergency transport. A computed tomography scan revealed an intracranial hypo-attenuated mass exhibiting mass effect. Several calcied foci were observed around the lesion. He suddenly showed tonic seizure after admission, therefore an emergency craniotomy was performed. However, he unfortunately died due to advanced cerebral oedema. Microscopic ndings of the surgically obtained materials were consistent with neurenteric cyst (NC). Intracranial hard masses were found adjacent to NCs and the masses were composed of brous cartilage-like matrix with massive linear calcication and surrounding round-to-oval epithelioid cells. NC was considered most appropriate diagnosis of present case. To the best of our knowledge, this is the rst report of such case. The present case suggests that delay of treatment may cause a poor outcome, at least in CAPNON associated with NC. Careful investigation, including of the pathology, essential deciding


Introduction
Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare calci ed tumefactive lesion that can occur in the brain or spine [1][2][3]. The growth of CAPNON is generally indolent, and the majority of reported cases show a benign clinical course after complete or subtotal surgical excision [2,3]. Therefore, the aetiology and natural course of CAPNON has not yet been fully established. A recent study reported that many CAPNON cases have dual pathology, which may be associated with its aetiology [1]. Here, we report a rare autopsy case of CAPNON that was completely free of any medical interventions in the critical period and was associated with a neurenteric cyst (NC), which is an endoderm-derived congenital lesion [4].

Case Report
A 53-year-old man complaining of head pain, systemic paralysis, and seizure in both legs was taken to Toyama Prefectural Central Hospital by emergency transport. Approximately 13 years previously, he had visited Toyama University Hospital because of hyposmia and headache. Imaging examination revealed a calci ed mass in the left anterior cranial base (Fig. 1a-e). Although surgical treatment was proposed, he refused surgery and did not visit the hospital again. According to his family, his personality gradually changed and he had started to complain of several additional symptoms in the last few years, including dizziness, tinnitus, and neck pain. He had also shown abnormal behaviour in the last few months, such as suddenly screaming or talking to strangers. At the time of emergency transport, his consciousness was clear and conversation was possible. A computed tomography scan revealed an intracranial hypoattenuated mass without enhancement, exhibiting mass effect ( Fig. 1f-j). Additionally, several calci ed foci were observed around the lesion. At midnight of the day he was hospitalized, he suddenly showed tonic seizure and anisocoria (2 mm and 4 mm on the right and left pupils, respectively); the neurosurgeon therefore decided to perform an emergency craniotomy. During surgery, a cystic lesion containing pus-like uid and semisolid brittle whitish materials was observed (Fig. 2a). Partial resection of the lesion and internal and external decompression were performed. However, cerebral oedema progressed continuously despite intensive care, and he died 12 days after surgery.
Microscopic examination of the cystic lesion revealed a single layer of ciliated columnar epithelium without cellular atypia (Fig. 2b). These ciliated columnar cells were positive for cytokeratin 7 and 20 but negative for glial brillary acidic protein and S-100 ( Fig. 2c-f) (Table 1). Cytological examination of the intra-cystic uid identi ed no malignant cells. These ndings are consistent with NC.
At autopsy, a large bone defect was observed in the midline of the anterior cranial fossa (Fig. 3a). The brain weighted 1542 g and exhibited severe encephalomalacia. Moreover, there were several hard masses, mainly in the left frontal lobe.
Microscopically, the hard masses were composed of brous cartilage-like matrix with massive linear calci cation and partial ossi cation (Fig. 3b). NCs were also observed adjacent to hard mass lesions ( Fig. 3c). Various pathological appearances containing collagen bres and hyaline cartilage-like stroma were identi ed beneath the hard masses (Fig. 3d). Here, there were foci of granulation tissue, containing abundant lymphocytes and macrophages, and necrotic tissue with marked neutrophil in ltration (Fig. 3e).
The hard masses were surrounded by round-to-oval epithelioid cells and giant cells (Fig. 3f).

Discussion
Supratentorial NC is rarely associated with calci cation [4], and we were unable nd any previous report of obvious mass lesions associated with NC. We consider that CAPNON associated with NC is the most appropriate pathological diagnosis of the present case; To the best of our knowledge, this is the rst report of CAPNON associated with NC. The enlarged and newly appeared calci ed lesions and the enlargement of the NC con rmed before surgery demonstrated that CAPNON development may have been associated with congenital NC in the current case. Prolonged and/or recurrent in ammation of NC and/or its secretion product in the present case might have contributed to the enlargement of NC itself, and might thus contribute to the occurrence and development of CAPNON. It is notable that synovial cysts are frequently associated with spinal CAPNON [1]. Therefore, investigations targeting cystic lesions may be important for examining the aetiology of CAPNON.
In the present case, slowly progressive cerebral oedema caused by the development of CAPNON and associated local in ammation may have gone beyond the irreversible level because of the long-term untreated period. Necrosis of pituitary glands is also associated with advanced brain oedema, and may cause pituitary apoplexy in the terminal phase. The present case demonstrates the importance of early surgical resection for CAPNON, even though the clinical course of CAPNON is essentially benign [1].
Careful investigation of the association between NC and CAPNON is needed, and complete resection of NC may be essential when NC is found beneath CAPNON.
Although we identi ed epithelioid cells that were positive for epithelial membrane antigen and vimentin, as shown in a previous report [3], the lesion should not be diagnosed as meningioma because these cells are also positive for various markers, including S-100, glial brillary acidic protein, nestin [5], and histiocytic markers such as CD68 and CD163 [6]. The immunohistochemical appearance of the present case, especially in the expression of SSTR2, which is the most sensitive and speci c marker for meningiomas [7], was different from that previously shown in meningiomas. SSTR2 may thus be a useful marker for the differential diagnosis of CAPNON and calci ed meningiomas. Interestingly, although the meningothelial cells are one of the possible candidates for the origin of CAPNON [1], the immunohistochemical results between CAPNON and meningothelial hyperplasia in this study were quite different. Thus, CAPNON may be a condition different from mere meningothelial hyperplasia and further investigation is needed to identify its origin and pathogenesis.
In conclusion, we reported a case of fatal CAPNON that was likely associated with NC; marked cerebral oedema related to prolonged local in ammation was evident in the brain. The present case suggests that no treatment may cause a poor outcome, at least in some CAPNON cases-and especially when CAPNON is associated with NC. Careful investigation, including of the underlying pathology, may be essential for deciding treatment strategies for CAPNON.