—  SPECIALTY CONFERENCE  —

Neuropathology

Case 4 - Calcifying Pseudotumor of the Neural Axis

B.K.Kleinschmidt-DeMasters, M.D. University of Colorado Denver, Denver, CO


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Clinical History
The patient is a 46 year old male who presented with approximately 1-2 years of shaking in the right hand, which progressed to increasing clumsiness of the hand, with dropping things. This prompted a visit to a neurologist. Neuroimaging studies showed several non-contiguous, intracerebral, non-dural based abnormalities in the left frontal lobe, associated with cerebral edema. These were interpreted as likely to be metastatic carcinoma or infectious in etiology.


Case 4 - Slide 1
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Case 4 - Figure 1
Neuroimaging study of the lesions
Case 4 - Figure 2
Low power photomicrograph of the well-demarcated lesion, 4X
Case 4 - Figure 3
Medium power photomicrographs illustrating features of the lesion, 10X.

Case 4 - Figure 4
Medium power photomicrographs illustrating features of the lesion, 10X.
Case 4 - Figure 5
Medium power photomicrographs illustrating features of the lesion, 10X.

Case 4 - Figure 6
Reticulin stain at interface between lesion (right) and brain (left), 20X
Case 4 - Figure 7
Trichrome stain at interface between lesion (left) and brain (right), 20X. Note Rosenthal fiber (red).


Diagnosis
Calcifying Pseudotumor of the Neural Axis

Discussion
This well-demarcated, non-infiltrative lesion was one of three identified on neuroimaging studies in this patient's brain; two of these are illustrated by the magnetic resonance imaging T2-weighted FLAIR image seen in (Case 4 - Figure 1). The low signal intensity of the two lesions seen could be explained by old blood products or dense calcification/ossification; the latter proved to be the case. The hyperintense (pale white) signal around the lesions likely represents mild edema, +/- gliosis, but there is little mass effect and neoplasm is unlikely given the volume of the signal around the lesion and yet no mass effect.

Similarly, on the microscopic slide supplied for this case, the mass was discrete and while surrounded by intense gliosis (Case 4 -Figure 2), there was a notable absence of cytological atypia in the astrocytes. Rosenthal fibers were present on H&E and highlighted by trichrome stain (Case 4-Figure 7), but no features of pilocytic astrocytoma were discernable. No vascular malformation was identified.

Medium power photomicrographs (Case 4 - Figures 3-6) revealed a nodule composed of basophilic material. Centrally, the hypocellular, chondroid-like matrix was more loosely arranged. Cells within the matrix did not reside within lacunae, were spindle to polygonal shaped, and lacked cytological atypia or mitotic activity (Case 4-Figures 3, 4). At the periphery of the nodule, the unique matrix was more dense and could be characterized as "coarsely fibrillar, hematoxylinophylic matrix, reminiscent of chicken footprints" [1] The periphery of the nodule was rimmed by a palisade of nuclei (Case 4-Figures 4, 7). Delicate, granulation tissue type blood vessels (Case 4-Figure 3) were identified centrally in the nodule, as was well-formed bone (Case 4-Figure 5), and non-neoplastic, non-granulomatous lymphocytic inflammation. No extramedullary hematopoiesis was present within the bone. Calcifications were seen (Case 4-Figure 2), but whorls and fascicles of meningioma cells were not identified and calcifications lacked the concentric appearance of true psammoma bodies. The volume of bone in the resected material overshadowed the calcification, suggesting that much of the signal seen on MRI was due to the ossification. Abundant linear reticulin fibers were present throughout the lesion (Case 4-Figure 6). Very focally the lesion could be seen to abut subpial and leptomeningeal regions of brain.

Additional histochemical and immunohistochemical staining was undertaken. The material was Alcian blue positive. The cells within the matrix, including those at the palisaded perimeter, were immunonegative for EMA (m, 1:100, Dako), GFAP, AE1/AE3, TP53, and S-100. CD45 labeled the numerous inflammatory cells. CD68 labeled scattered multinucleated giant cells. MIB-1 labeling was seen, but was largely confined to the lymphocytes, macrophages/multinucleated giant cells, and spindled fibroblasts between, but not within, the matrix itself.

1. What is the diagnosis?
The diagnosis is fibro-osseous lesion of the central nervous system, also known as calcifying pseudotumor of the neural axis. [1, 2, 3, 4, 5, 6, 7] This uncommon lesion was first reported in 1978 [4], and as of the last literature reviews on the topic published in 1999 and 2000, only 27 cases had been described. [1, 2]

Both intra- and extra-axial lesions occur. The most common occurrence is along the vertebral column in the epidural space (11/27 cases) or intracranially (16/27) at the skull base. [1]All levels of cord (cervical, thoracic, lumbar) can be affected. Intracranial examples have usually been extra-axial (10/27 cases). [1] Intra-axial, intracranial locations (ie within brain itself), such as this case, are the least frequent location for the lesions. Even in these cases, however, there may be a suggestion of a relationship with leptomeninges. Rare examples are completely intraosseous. [2]

Most patients harbor solitary lesions, although multiplicity is well described, as was seen in the current case. Lesion size varies from microscopic to 10 cm. in diameter. The age range of affected patients is broad (12-83 years, mean 46 years). [1] Many patients present with seizures, as did this patient. Lesions are slow growing and prognosis is excellent with gross total excision.

2. What is the differential diagnosis for this lesion?
The features of the matrix in calcifying pseudotumor of neural axis are stereotypic and almost negate any other diagnostic consideration, although the amount of additional calcification and ossification has varied considerably in reported cases.

Therefore, differential diagnostic considerations should really be broken down into several questions:

3. What is the differential diagnosis for relatively localized calcified nodules in the brain parenchyma/meninges?
a. Meningioangiomatosis: Tsuga and colleagues [3] note that some cases in the literature described as "unusual fibro-osseous lesion of the brain" have had overlapping features with meningioangiomatosis. [7] The case they reported [3], like ours, lacks the meningothelial cell proliferation and vascular component of meningioangiomatosis.

b. Psammomatous meningioma: Psammomatous meningiomas can possess large numbers of concentric calcifications that can coalesce. Dense calcifications can almost completely replace the meningioma cells. Psammomatous meningiomas are typically found in thoracic spinal cord dura, a feature that could overlap with sites affected by some examples of calcifying pseudotumor of neural axis. Careful histological examination eliminates the possibility of an underlying meningioma component. In addition, the calcifications seen in calcifying pseudotumor of neural axis are specifically noted NOT to have concentric psammomatous features. [1]

c. Primary or metastatic tumors with extensive calcification: Less than 1% of metastases are said to be significantly calcified. Many primary brain tumors calcify and could be included in the neuroradiological differential diagnosis, although in this specific case the absence of mass effect despite that volume of FLAIR signal abnormality would argue against a primary neoplasm. Indeed primary brain tumor was not high on the differential for the radiologists at the outside hospital from which this case was submitted. Ultimately however, tumor would have to be excluded based on the microscopic features present in the brain tissue surrounding this calcifying nodule. Specifically in this USCAP case, there was no cytological atypia or pilocytic features in the gliosis surrounding the nodule, despite the presence of Rosenthal fibers. Primary intra-axial brain tumors seldom calcify extensively enough to be considered "brain stones". More often, the MRI appearance reveals that the calcification is only one component of the lesion and the background neoplasm is not completely overshadowed. Examples of primary intra-axial tumors that can show extensive calcification include oligodendroglioma and neurocytoma. Other types of frequently calcifying primary brain tumors include choroid plexus papilloma, ependymoma, ganglion cell tumors, supratentorial primitive neuroectodermal tumors, and astrocytoma.

d. Extensive calcification can also occur in a primary brain tumor after the patient has been treated with radiation and/or chemotherapy.

In the literature, heavily calcified, very discrete nodules of calcium are sometimes referred to as "brain stones" or brain "calculi". Two more considerations for discrete nodular calcification in the brain are toxoplasmosis and cavernous angiomas.

e. Toxoplasmosis, particularly in the adult, can result in variable numbers of discrete calcifications within the brain after demise of the parasite, following either spontaneous resolution of the infection or anti-toxoplasmosis treatment. No fibrotic abscess capsule or inflammatory granulomatous response was present. The basophilic matrix in this case is not typical for calcified, remote toxoplasmosis lesions.

f. Vascular malformations: Small vascular malformations, usually cavernous angiomas, can show almost obliterative calcification or ossification, but usually some non-mineralized, non-ossified portion of the lesion remains at the histological level that allows for an accurate diagnosis. No vascular malformation was present in this case. Vessels that were present were capillaries that appeared to be reparative and granulation tissue like.

4. What is the differential diagnosis for relatively localized ossified nodules in the brain parenchyma/meninges?
Because fibro-osseous lesions of the neural axis can have a predominantly ossified portion, as did this case, a differential for discrete ossification within the brain or dura also has to be raised.

g. Ossification: Discrete, benign ossification occurs in the CNS, with or without an associated neoplasm; both conditions are infrequent. Dystrophic ossification is most commonly encountered in the dura, with the classic examples being untreated chronic subdural hematomas, chronic infections, or post-surgical change. Dystrophic ossification resembles normal bone, usually does not show extramedullary hematopoiesis, and is not associated with the unusual fibrillar matrix seen in the current USCAP case.

h. Ossification within neoplasm: Meningiomas may show metaplastic bone formation but the absence of meningothelial cells, either in fascicles or whorls, negates this consideration. Osteosarcoma has rarely been reported as a primary, pure lesion in brain parenchyma. Bone can also be found within the sarcomatous portion of a gliosarcoma, either pretreatment or after radiation and chemotherapy. [8] Not only the surrounding brain, but the bone itself in this USCAP case was quite cytologically bland.

5. Since this case had multiple lesions in the brain are there any systemic disorders associated with mineralization that one should consider in the differential?
Inherited tumor syndromes or systemic metabolic disorders can be associated with calcifications. In the case of inherited tumor syndromes, the calcifications tend to be relatively stereotypical in their location and be associated with additional clinical features.

i. Of the various inherited familial tumor syndromes Gorlin syndrome might be a consideration because of its tendency to cause dural calcifications, particularly in the falx (8/9 cases) and tentorium (9/9). [9] But Gorlin patients seldom undergo computerized tomographic scans, the neuroimaging study most likely to reveal calcifications, due to radiation exposure potentially causing squamous cell and basal cell carcinomas in this vulnerable population.

j. In terms of parenchymal brain calcifications in systemic conditions, most mineral deposits are symmetrical within the brain and favor the basal ganglia as at least one of the sites of involvement. Fahr's disease is a non-atherosclerotic Ca++ deposition usually maximal in the basal ganglia and dentate nuclei. Microscopically, much of the Ca++ deposition is associated with small blood vessels. [10] Marble brain disease is an autosomal recessive disorder manifesting as renal tubular acidosis, cerebral calcifications and osteopetrosis. [11] It has usually has been reported in individuals from the Mediterranean or Middle East and is due to carbonic anhydrase II deficiency; mental retardation is seen in most patients. Hypoparathyroidism can lead to multifocal brain calcifications which are usually symmetrical and particularly affect basal ganglia, thalami, internal capsule, and posterior fossa although cerebral hemispheric lesions can be seen. [12] Multifocal intracranial calcifications are characteristic of brain injury that occurs in the perinatal time period, most notably after infections or hypoxic-ischemic damage. Calcifications seen in brain with TORCH syndrome are usually also associated with microcephaly and life-long cognitive problems, neither of which was present in this case. Perinatal hypoxia-ischemia calcifications often affect basal ganglia. [13] An esoteric disorder, Labrune's disease (Coat's plus), was a diagnostic consideration for us on this case, since not only calcifications but profuse Rosenthal fiber deposition can occur in the gliosis adjacent to the calcifications in that disorder. [14] However, Labrune's is further associated with brain cysts and unusual vasculature, which were not present in the current USCAP case.

6. What is the differential diagnosis for relatively localized matrix-rich lesions?
k. From a purely morphological viewpoint, most pathologists would probably consider some type of chondroid-containing process, given the basophilic matrix. However, the matrix is more coarse and fibrillar than that seen in chrondrosarcomas or chondromas and cells located within lacunae were not present.

7. What other "inert-omas" might I consider in my differential diagnosis?
Amorphous material, especially focal within brain parenchyma, is uncommon but spontaneously occurring, non-surgically induced inert tissue deposits-- "inert-omas"-- can be broken down into the crude categories of eosinophilic and basophilic entities. The more common considerations will be discussed here.

Eosinophilic entities include localized amyloidoma and large proteinaceous deposits in brain parenchyma after radiation and chemotherapy. Basophilic entities are usually basophilic due to their superimposed mineralization and include xanthogranulomas of the choroid plexi and cholesterol granulomas of the bony skull base. Basophilic mineralization and refractile material can be seen in Gamna-Gandy bodies.

l. Amyloidoma: In 2006, a beautiful case of localized mass-like amyloidoma was presented at this USCAP neuropathology night panel by Dr. Suzanne Powell. I refer you to the case 3 images and discussion for comparison with the current case. Amyloid displays apple-green color under polarization; the coarsely fibrillar material does polarize, but the birefringence is due to the collagenous content of the lesion.

m. Fibrinous exudate in brain parenchyma: Proteinaceous fibrinous deposits within brain sometimes are quite striking following vascular injury in severe radiation and chemotherapy-induced brain damage. These deposits are eosinophilic, less dense than amyloid, and never fibrillar. The material is associated with fibrinoid damage to nearby blood vessels and a history of radiation therapy is usually obtainable.

n. Xanthogranuloma of choroid plexi: I refer you to the 2005 neuropathology night panel case presented by Dr. Greg Fuller, case 3. Cholesterol clefts, hemosiderin and hematoidin pigment, macrophage influx, and fibrosis can be found in these lesions despite the extensive mineralization. The lesions are due to bleeding into the choroid plexus.

o. Cholesterol granuloma of bone: Lesions of the bone, usually in the skull base, show histological features similar to xanthogranuloma of choroid plexus, although admixed destroyed bone may also seen. [15]

p. Gamna-Gandy bodies: These fascinating entities are a form of dystrophic mineralization defined as "spheroidal yellow-brown foci consisting of dense fibrous tissue and collagenous fibers incrusted with iron pigments and basophilic calcium salts". [16] These siderotic nodules were first described in the spleen early in the 20th century and for a short time were considered to be caused by fungal infection due to the presence of unusual "bamboo-like and articulated" fibers in the lesions that vaguely mimicked mycelia forms. This notion was proven to be incorrect in the 1930s and the bodies are now considered to result from organization of small hemorrhages. Examples are not infrequent in surgical neuropathological practice and can be found in a number of different neoplastic, and even non neoplastic processes, in the CNS that share a tendency for repetitive re-bleeding. The "bamboo-like and articulated" fibers are lacking in the current USCAP case under discussion. Nevertheless, there may be similarities between G-G bodies and calcifying pseudotumors in that both may be dystrophic in origin

8. What is the likely etiology for calcifying pseudotumor of the neural axis?
The etiology of calcifying pseudotumor is poorly understood. The likely cell of origin is the arachnoidal cell, fibroblasts, or some other type of mesenchymal cell, particularly given the common association with dura or leptomeninges. [1]The entity may represent a benign, overly exuberant and unusual non-neoplastic proliferative process. It is not thought to be neoplastic and prognosis is excellent if gross total excision is achieved although some skull base examples have been associated with considerable morbidity.

9. So if this is reparative and dystrophic, does calcifying pseudotumor of the neural axis resemble other systemic lesions?
If one had to suggest what the coarse, basophilic fibrillar material most resembles, it would have to be calcium pyrophosphate, similar to the dystrophic changes seen in articular cartilage in elderly persons. Similar material can be seen in synovial excrescences of the spine. [17] Hence, it may be deposited in mesenchymal tissues as a reparative phenomenon. What the instigating event, if any, was in this particular patient is unknown. The lesion also shows some similarities with calcifying aponeurotic fibroma, which can arise in unusual sites. [18]

Take Home Points
  • This is a rare entity with pathognomonic features of discrete, hypocellular nodule(s) of coarsely fibrillar, basophilic matrix with palisading of nuclei at the perimeter. The amount of calcification and ossification varies.

  • Most reported lesions have occurred along the vertebral column or in dura/leptomeninges at the skull base.

  • The entity is non-neoplastic, probably proliferative and reparative. Prognosis is excellent with complete surgical excision.

References
  1. Qian, J, Rubio A, Powers, JM, Rosenblum MK, Pilcher WH, Shrier DA, Stein BM, Ito, M, Iannucci A. Fibro-osseous lesions of the central nervous system: report of four cases and literature review. AJSP 23(10), 1270, 1999.

  2. Chang H, Park J-B, Kim K-W. Intraosseous calcifying pseudotumor of the axis. Spine 25, 1036, 2000.

  3. Tsugu H, Fukushima T, Takeno Y. Calcifying pseudotumor of the neural axis. Neurol Med Chir (Tokyo) 39: 762-765, 1999.

  4. Rhodes RH, Davis RL. An unusual fibro-osseous component in intracranial lesions. Hum Pathol 9:309-19, 1978.

  5. Bertoni F, Unni KK, Dahlin DC, Beabout JW, Onofrio BM. Calcifying pseudoneoplasms of the neural axis. J. Neurosurg 72:42-8, 1990.

  6. Jun C, Burdick B. An unusual fibro-osseous lesion of the brain. J. Neurosurg 60:1308-11, 1984.

  7. Halper J, Scheithauer BW, Okazaki H, Laws ER. Meningio-angiomatosis: a report of six cases with special reference to the occurrence of neurofibrillary tangles. JNEN 45:426-46, 1986.

  8. Kleinschmidt-DeMasters, B.K., Kang, J.S., Lillehei, K.O. The burden of radiation-induced CNS tumors–a single institution's experience. J Neuropathol Exp Neurol 65(3):204-16, 2006.

  9. Friedrich RE. Diagnosis and treatment of patients with nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome). Anticancer Research 27:1783-7, 2007.

  10. Kobayashi S, Yamadori I, Miki H, Ohmori M. Idiopathic nonarteriosclerotic cerebral calcification (Fahr's disease): an electron microscopic study. Acta Neuropatholgoica 73:62-6, 1987.

  11. Cotter M, Connell T, Colhoun E, Smith OP, McMahan C. Carbonic anhydrase II deficiency: a rare autosomal recessive disorder of osteopetrosis, renal tubular acidosis, and cerebral calcification. J. Ped Heme/Onc 27:115-7, 2005.

  12. Kowdley KV, Coull BM, Orwoll ES. Cognitive impairment and intracranial calcification in chronic hypoparathyroidism. Amer J.Med Sci 317:273-277, 1999.

  13. Rodriguez MJ, Ursu G, Bernal F, Cusi V, Mahy N. Perinatal human hypoxia-ischemia vulnerability correlates with brain calcification. Neurobiol Disease. 8:59-68, 2001.

  14. Corboy, J.R., Gault, J., Kleinschmidt-DeMasters, B.K. An adult case of leukoencephalopathy with intracranial calcifications and cysts. Neurology 67(10):1890-2, 2006.

  15. Sze, C.I., Huffer, W., Breeze, R., Escott, E., Kleinschmidt-DeMasters, B.K. Intracalvarial cholesterol granulomas—clinicopathologic correlates of three cases. Clin Neuropathol, 22(1): 41-46, 2003.

  16. Kleinschmidt-DeMasters, BK., Gamna-Gandy Bodies in Surgical Neuropathology Specimens: Observations and an Historical Note. JNEN, 63 (2); 106-112, 2004.

  17. Sze, C.I., Huffer, W.B., Kindt, G., Chang, M., Wang, M., Kleinschmidt-DeMasters, B.K., Synovial excrescences and cysts of the spine: distinctive clinico-pathological features and role in causation of spinal stenosis, Clin Neuropathol, 23(2):80-90, 2004.

  18. Fetsch JF, Miettinen M. Calcifying aponeurotic fibroma: a clinicopathologic study of 22 cases arising in uncommon sites. Hum Pathol 29:1504-10, 1998.