Collision Lesions of Calcifying Pseudoneoplasm of the Neuraxis and Rheumatoid Nodules: A Case Report With New Pathogenic Insights

Introduction

Calcifying pseudoneoplasms of the neuraxis (CAPNON) is a rare tumor-like lesion that can occur anywhere in the neuraxis including the brain and spine.^1-3 Since CAPNON was first characteristically described in 1978, ⁴ more than 100 cases have been reported in the literature.^2,3,5,6 However, its prevalence is likely underestimated, since there have been a few previously reported cases of incidental CAPNONs and diagnostic challenges to identify CAPNON. ⁶ The preoperative diagnosis of CAPNON is difficult as its radiological features are nonspecific.^3,5,7,8 CAPNON is diagnosed by pathological examination revealing a collection of histopathological features: granular amorphous confluent cores with dystrophic calcification/ossification, peripheral palisading spindle to epithelioid cells, variable fibrous stroma, and foreign-body reaction with multinucleated giant cells.^3,5-10 While one study described CAPNON lesions as granulomas/granuloma-like masses, ¹ and some other studies considered granulomatous inflammation in the differential diagnosis for CAPNONs,^5,11 there has been no report of association between CAPNONs and granulomatous inflammatory diseases or lesions such as rheumatoid nodules (RNs).^12-14

The pathogenesis of CAPNON remains elusive, since there have been a few hypotheses including a reactive process,^{1-3,6,7,15-19} degenerative process, ¹⁰ metaplastic transformation, ²⁰ metabolic dysfunction, ¹¹ and neoplasm. ⁴ The hypothesis of a reactive process associated with inflammation and/or injury has been favored,^{1-3,6,7,15-19} but there have been no observational studies to support this hypothesis and an immune-mediated process has been recently hypothesized.^21,22 There have been several cases of CAPNONs associated with neoplasms, including dysembryoplastic neuroepithelial tumor, ¹⁵ ependymoma, ¹⁶ low-grade glioma, ¹⁷ meningioma, ¹⁸ and lipomas.^19,21,22 This association of CAPNONs with neoplasms is a collision or continuity of 2 lesions.^15-19,21,22 Up to date, no collision of CAPNON with a non-neoplastic lesion has been reported. Here we report a unique case of collision of CAPNON with RNs, which provides some insights into the pathogenesis of CAPNON.

Case Report

The patient was a 51-year-old female who presented with lower back pain and subsequently a lower back mass that was initially stable and then slowly grew over 2 years. Her past medical history was significant for systemic lupus erythematosus (SLE) with associated blindness and SLE glomerulonephritis, scleroderma, associated interstitial lung disease, end-stage renal disease on dialysis, right arteriovenous fistula for dialysis, secondary hyperparathyroidism, osteoporosis, hypertension, hyperlipidemia, uterine fibroids, anemia, and bilateral cataracts. Her SLE was diagnosed 21 years ago when she presented with rash, arthralgia, psychosis, Raynaud’s phenomenon, and kidney involvement. Her kidney disease was diagnosed by pathological examination as class IV and V lupus nephritis for which she was treated with cyclophosphamide and mycophenolate for a short term. She was then on prednisone for these years and multiple other medications. In the past years, she had 3 skin biopsies that revealed chronic dermatitis of the left big toe, capillary hemangioma in the right flank, and compound nevus of the right scapula. The abdominal/pelvic computed tomography scan 9 years ago and head magnetic resonance imaging 3 years ago were unremarkable. Seven months after her presentation of the lower back pain, an abdominal ultrasound showed a subcutaneous complex lesion measuring 4 cm in maximal dimension with calcifications and cystic spaces. Eight months later, physical examination revealed an elliptical mass that was firm and nonmobile, measuring 5 cm in maximal dimension (superior to inferior) over the center of her lower back. Spinal magnetic resonance imaging without contrast revealed a heterogeneous mass, measuring 5.8 × 5.1 × 4.8 cm, centered in the paravertebral fascia in the midline at the levels of L3-4 vertebral bodies. The mass was predominantly hypointense on T1-weighted images, mixed hypointense and hyperintense on T2-weighted images, and heterogeneous on proton density fast spin-echo images with calcifications and multiple fluid sensitive sequences (Figure 1A-D). She underwent an ultrasound-guided biopsy of the mass.

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Figure 1.

Magnetic resonance T1-weighted sagittal (A) and axial (B), T2-weighted sagittal (C), and axial proton density fast spin-echo (D) images show a large heterogeneous mass (arrowed) with calcifications and multiple fluid sensitive sequences in the paravertebral fascia in the midline at the levels of L3-4 vertebral bodies.

The biopsy specimen was formalin-fixed, routinely processed, paraffin-embedded, sectioned at 5 µm, stained with hematoxylin and eosin, and by immunohistochemistry. Automated immunohistochemistry was performed on tissue sections using the Dako Autostainer Link 48 and visualized with the Dako Envision Flex kit detection system (Dako). Our present study used the following antibodies: CD68 (KP1, Dako), CD8 (C8/144B, Dako), CD4 (4B12, Dako), and CD20 (L26, Dako).

Microscopic examination of the biopsied tissue revealed fibrous connective tissue containing granular amorphous or dystrophic calcified cores with palisading spindle to epithelioid cells, fibrous stroma, and scattered CD68+ macrophages including occasional multinucleated giant cells (Figure 2A and B), which was consistent with CAPNON.

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Figure 2.

Photomicrographs of biopsied CAPNON (calcifying pseudoneoplasm of the neuraxis) exhibit granular amorphous or dystrophic calcified cores with palisading spindle to epithelioid cells, fibrous stroma (A), and scattered CD68+ macrophages (B), including occasional multinucleated giant cells (A, arrowed; and B). Original magnification, ×100 (A), and ×400 (B, inset in A).

After the biopsy, that mass increased in size over the following 5 months. On physical examination, it was still nonmobile, nontender, and firm; neurological examination was unremarkable. A noncontrast computed tomography showed a midline well-defined, densely calcified mass, measuring 6.5 × 5.6 × 5.6 cm, centered in the spinal musculature at the L4 level with a few noncalcified soft tissue components, full involvement of the spinous process, and focal invasion into the adjacent tissue (Figure 3A-C). She underwent the open surgery making approximately a 10-cm midline incision (Figure 3D and E), and the mass was resected en bloc (Figure 3F).

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Figure 3.

Computed tomography sagittal (A), axial (B), and coronal (C) images demonstrate a midline well-defined, densely calcified mass centered in the spinal musculature at the L4 level with a few noncalcified soft tissue components, full involvement of the spinous process, and focal invasion into the adjacent tissue. Surgical resection makes approximately a 10 cm midline incision (D); shows the mass in situ (E) and resected en bloc (F).

The resection specimen was processed and examined by the same methods, as described above. Electron microscopy (EM) was also performed on a portion of the tissue that was fixed in 2% glutaraldehyde, postfixed in 1% osmium tetroxide, dehydrated, and embedded in resin. Ultrathin sections were stained with uranyl acetate followed by lead citrate and examined with JEOL 1230 Transmission electron microscope.

Microscopic examination of the resected tissue revealed the features similar to those of the previous biopsy (Figure 4A; consistent with CAPNON), multiple nodules of granulation tissue (Figure 4B; consistent with the first stage of RN ¹² ), nodular lesions with granulomatous inflammation (Figure 4C; consistent with the second stage of RN ¹² ), and/or central necrosis (Figure 4C,4D; consistent with the third stage of RN ¹² ), inflammatory nodules adjacent to calcified lesions (Figure 4E), necrotic lesions with direct continuity to calcified lesions (Figure 4F), and transitional lesions with combined nodular inflammatory/necrotic lesions and calcified foci (Figure 4G). Von Kossa staining highlighted heavy mineralization/calcification in the CAPNON lesions, but early focal mineralization/calcification in RN to transitional lesions and in perivascular areas (Figure 4H). CD68+ macrophages were focally abundant in nodular inflammatory lesions (Figure 4I) but relatively infrequent in calcified lesions and their adjacent tissue (Figure 4J). There were focally frequent CD8+ cytotoxic T-cells (Figure 4K) with much less CD4+ T-cells (Figure 4L) and CD20+ B-cells (not shown). EM demonstrated tubuloreticular inclusions in the endothelial cells of blood vessels (Figure 4M), which is in keeping with SLE in this patient.

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Figure 4.

Photomicrographs of combined CAPNON (calcifying pseudoneoplasm of the neuraxis) and rheumatoid nodule (RN) lesions. CAPNON lesions show granular amorphous or dystrophic calcified cores with palisading spindle to epithelioid cells, fibrous stroma, and occasional multinucleated giant cells (A, arrowed), RN lesions include a nodule of granulation tissue (B, labelled 1; consistent with the first stage of RN), a nodular lesion with granulomatous inflammation (C, labelled 2; consistent with the second stage of RN) and focal necrosis (C, labelled 3; consistent with the third stage of RN), and a completely necrotic lesion (D, labelled 3, compared with the right calcifying areas). Some other lesions exhibit a calcified lesion (E, labelled *) adjacent to an inflammatory nodule (E, labelled 1, also shown in B), a necrotic focus (F, labelled 3) with direct continuity to a calcified lesion (F, labelled *), and a transitional lesion with combined nodular inflammatory and calcified foci (G, labelled *). Von Kossa staining highlights heavy mineralization/calcification in the CAPNON cores (H, right), but early focal mineralization/calcification in RN to transitional lesions (H, left) and in perivascular areas (H, inset). CD68+ macrophages are focally abundant in inflammatory nodules/lesions (I, labelled 2/3) but relatively infrequent in calcified lesions and their adjacent tissue (J, labelled *; compared with an inflammatory nodule, labelled 2). There are focally frequent CD8+ cytotoxic T-cells (K) with much less CD4+ T-cells (L). Electron microscopy reveals tubuloreticular inclusions in the endothelial cells of blood vessels (M), which is in keeping with systemic lupus erythematosus in this patient. Original magnification, ×100 (E and H), ×200 (A-D, F, G, and I-L), and ×40 000 (L).

Discussion

This case report is the first to demonstrate collision lesions of CAPNONs and RNs in the patient with SLE. RNs are inflammatory lesions associated with reactive changes^12-14,23; SLE is an autoimmune disease involving multiple organs and systems including the paravertebral and adjacent tissue^23,24 that is the location of collision lesions in our present case. This case shows collision lesions and transitional lesions of CAPNONs and RNs with immune cell infiltrates, which may suggest an immune-mediated reactive process in the pathogenesis of CAPNON.

Collison lesions are rare and composed of 2 histologically distinct lesions arising from the same anatomic site. CAPNONs have been occasionally reported in collision with dysembryoplastic neuroepithelial tumor, ¹⁵ ependymoma, ¹⁶ low-grade glioma, ¹⁷ meningioma, ¹⁸ and lipomas.^19,21,22 These collision lesions are CAPNONs associated with neoplasms, and except a meningioma, intra-axial lesions. The observation of these collision lesions provides direct evidence for an reactive process in the pathogenesis of CAPNONs.^15-19 Two recently reported cases of CAPNONs with lipomas and the agenesis of the corpus callosum have shown immune cell infiltrates including M2 macrophages with a high ratio of M2/M1 macrophages and a high uptake of 11C-methionine positron emission tomography, ²¹ as well as CD8+ cytotoxic T-cells with a decreased ratio of CD4/CD8+ T-cells, ²² which suggest an autoimmune process in CAPNONs. Our present case demonstrates CAPNONs in collision with inflammatory RNs and containing CD8+ cytotoxic T-cells with much less CD4+ T-cells in the patient with SLE, which provides additional evidence for an autoimmune process involved in CAPNON.

CAPNONs are located primarily in the neuraxis possibly with involvement of the adjacent soft tissue, while RNs are sited primarily in the subcutaneous tissue often with involvement of the dermis and bone.^14,23 Therefore, CAPNONs may share the locations with RNs particularly in the paraspinal regions. RNs are not only seen in rheumatoid arthritis but also found sometimes in the patients with SLE.^12,13,23 The patient in our case report had no evidence of rheumatoid arthritis but advanced SLE that was also evident in this resected lesion with the EM finding of tubuloreticular inclusions characteristic of SLE. In the lesion progression, RNs have 3 histopathological stages: an acute inflammatory stage, a granulomatous stage, and finally a necrotic stage. ¹² At the first stage, the RN lesion consists of an area resembling granulation tissue. The second stage of RNs is heralded by the development of necrosis and palisading of elongated mononuclear cells mostly macrophages at the periphery of the initial focus of granulation tissue. At the third stage, RNs are largely necrotic in the center with deposition of cellular debris and fibrinoid material. Mature RNs have classic 3-layer architecture, but typically no calcifications are seen in RNs.^12-14 In our present case, there are some transitional lesions with combined CAPNON and RN features; calcified lesions are more representative of CAPNON lesions, and non-calcified lesions are most consistent with RNs or precursors of CAPNON lesions.

Conclusion

As demonstrated in our present case, CAPNON may be in collision with RNs in patients with an autoimmune disease like SLE. Our findings of collision lesions and transitional lesions of CAPNONs and RNs, along with previously reported cases of collision lesions, suggest an immune-mediated reactive process in the pathogenesis of CAPNON.