3-10-2013 Intraventricular fibrous meningioma (WHO grade I)
Intraventricular meningiomas are uncommon tumors, accounting for < 3% of intracranial meningiomas. The atrium of the lateral ventricles is the most common site; examples of 3rd and 4th ventricular tumors are much less common. The tumors tend to occur in younger patients (i.e. 2nd to 4th decades). However, younger patients may be affected, including infants (think of neurofibromatosis type II!). Atypical tumors are uncommon.
Regarding the differential for intraventricular tumors, remembering what cells normally occupy (or lie adjacent to) that location will cover pretty much everything...
Choroid plexus: Choroid plexus papilloma/carcinoma
Arachnoid rests (in choroid plexus tufts): Meningioma
Ependyma: Ependymoma, subependymoma
Subependymal glia: SEGA, gliomas
Neurons: Central neurocytoma, PNET
Other: Colloid cyst (foramen of Monro), teratoma, Cysticercosis
In this case, the finding of a banal, spindled, collagen-rich neoplasm is consistent with a fibrous meningioma. The solitary Psammoma body (and nearly the same number of meningothelial whorls) seals the deal. Immunohistochemical staining consisted of a sole Ki-67 immunostain. None others were needed. By the time that I realized that I had posted two meningiomas in a row, it was too late to go back. Such is life.
10-3-2012 Atypical meningioma (WHO grade II); Neurofibromatosis type II
The neuroimaging demonstrates multiple extra-axial homogenously-enhancing dural-based tumors. In addition, the sagittal section demonstrates an enhancing cerebellopontine angle tumor. Here is a more informative image (intentionally withheld to increase case difficulty).
The H&E sections show a meningothelial meningioma. Thus, this patient has multiple meningiomas and bilateral acoustic "neuromas" (schwannomas), consistent with neurofibromatosis type II (NF2). Distinct from NF1, in which cutaneous manifestations predominate, NF2 shows a paucity or absence of cutaneous manifestations, and is referred to as "central neurofibromatosis". The syndrome results from mutations (or less often deletions) of the NF2 (aka merlin) tumor suppresor gene on 22p11.1 and is classically transmitted in an autosomal dominant fashion. Many causes result from de-novo mutations, and thus lack a positive family history.
Components of Neurofibromatosis type II are as follows:
Now, on to the specifics of this tumor. The tumor showed focal meningothelial whorls, consistent with meningioma. In addition, a finding that gets less attention in descriptions of meningioms are intranuclear pseudoinclusions, readily apparent in the second H&E image. Psammoma bodies may also be seen, but were rare and poorly-formed in this case. Meningiomas in patients with NF2 often behave in a more aggressive fashion, with an increased risk of tumor recurrence. Accordingly, this meningioma was designated as an atypical (WHO grade II) meningioma, a lesion with an increased risk of recurrence after resection. According to the WHO, one can arrive at a diagnosis of "atypical meningioma" by any of three routes
While not specifically indicated in the WHO criteria for an atypical meningioma, this tumor showed a greater degree of cytologic atypia than usually seen in a plain vanilla meningioma. In addition, the Ki-67 labeling index was 13.5%, also much greater than usual. I consider these worrisome features, and would communicate this information to the clinicians as "features worrisome for a more aggressive clinical course".
4-7-2012 "Black thyroid", Black discoloration of bone
http://www.jstage.jst.go.jp/article/internalmedicine/49/16/1835/_pdf
The finding of interest in this case was "charcoal black" discoloration of the otherwise unremarkable thyroid gland, as well as dark-brown discoloration of the inner aspect of the skull. This finding has been described in associated with long-term tetracycline (most often minocycline) ingestion. In this case, the previous minocycline therapy was most likely utilized for the treatment of bacterial endocarditis.
Besides bone and thyroid discoloration, there are reports of minocycline-induced black discoloration of teeth and, less often, of atherosclerotic plaques in large arteries. The etiology is uncertain. Proposed mechanisms include (but are not limited to) accumulation of oxidized minocycline breakdown products, inhibition of thyroid peroxidase, and interference with normal cellular degradation pathways (e.g. lysosomal). The clinical significance is uncertain, and likely minimal at best. Some authors report no clinical sequelae, others report hypothyroidism. Occurrences of neoplasia (papillary thyroid carcinoma, trabecular adenomas) in the setting of black thyroid are most likely incidental.
Histologic examination of the thyroid gland demonstrates accumulation of excess dark brown to black pigment in both the colloid and follicular epithelium. The thyroid epithelium is typically otherwise quiescent. Ultrastructurally, the accumulated material resembles lipofuscin; special stains typically positive in lipofuscin deposits (e.g. Fontana-Masson) are reportedly positive. Auto-fluorescence under fluorescent microscopy is also consistent with lipofuscin. Of note, lipofuscin normally accumulates in the thyroid glands (and diverse other organs) in aged individuals, just not to the extent of gross organs discoloration.
1-29-2012 Hydrophilic Polymer Emboli
http://www.ncbi.nlm.nih.gov/pubmed/19846823
http://www.ncbi.nlm.nih.gov/pubmed/20305613
This case was one in which I puzzled over the diagnosis for awhile before having that "Ah-ha!" moment. Infection with an endovascular parasitic organism was my prime consideration, but something just didn't seem right. Searching pubmed with descriptive terms yielded the correct diagnosis...
There are several reports of cases of embolization of the hydrophilic coating which ensheaths catheters used for endovascula procedures, in this case cerebral angiography. The purpose of the coating is to reduce friction and decrease the incidence of vasospasm. The two publications above (Mehta et al, Allen et al) describe several such cases. Unlike this case, in which the material was only seen in one sampled vessel and evidence of secondary damage was not seen, many of the reported cases show widespread embolization and subsequent tissue damage (e.g. ischemia, inflammation). Pathologically, the material is variably basophilic and lamellated, is non-refractile, does not polarize, and is often accompanied by a foreign-body type giant cell reaction.
12-27-2011 Chondroid chordoma
http://www.ncbi.nlm.nih.gov/pubmed/16604512
http://www.ncbi.nlm.nih.gov/pubmed/18055855
Chordomas are tumors which arise in areas associated with the embryonic notochord. The recognition of "conventional" chordomas is aided by the classic histologic finding of cords of "physaliferous (Greek--> "bubble bearing") cells". In examples such as this case, the majority of the tumor shows frank cartilaginous differentiation; only rare areas showed chordoid differentiation. The distinction between a well-differentiated chondrosarcoma and a chondroid chordoma requires immunohistochemistry. Owing to notochordal derivation, S100 is positive. Cytokeratin reactivity will distinguish a chordoma (+) from a chondroma/chondrosarcoma (-). Additional considerations include other neoplasms with chordoid features, notably a chordoid meningioma (will have areas of meningothelial differentiation).
A new immunohistochemical marker for the diagnosis of chordoma is currently being touted--> brachyury. A nuclear transcription factor identified by gene expression profiling, brachyury immunostains label the nuclei in a large percentage (90%) of chordomas, including chondroid chordomas. However, for practical purposes, as discussed above, a cytokeratin immunostain will suffice in the majority of cases.
The tumor behavior is characterized by local recurrence. Sarcomatous (de-differentiated) examples are rare. Of note, core biopsies of a suspected chordoid example is not indicated, as the tumors are relatively gelatinous and discohesive; tumor seeding of the biopsy tract or spread along traversed structures may be seen.
12-10-2011 Intraventricular ganglioglioma (WHO I)
http://www.ncbi.nlm.nih.gov/pubmed/19290468
http://www.ncbi.nlm.nih.gov/pubmed/18829326
While the neuroradiologic finding of a large irregularly-enhancing mass with significant surrounding T2 signal abnormality is worrisome, the intraventricular location and patient age are clues that the tumor may represent an indolent lesion, as in this case. The tumor comprised an intimate admixture of spindled, bland-appearing glial cells and dysplastic ganglionic cells, hence the designation ganglioglioma. The glial component lacked mitotic activity, and microvascular proliferation and necrosis were absent. Neuronal dysplasia was evidenced by abnormal clustering, increased cytologic pleomorphism, and rare binucleation.
Of note, ganglion-like cells within a glial population raises two possibilities: First, the ganglionic cells may represent entrapped pre-existing neurons in an infiltrative neoplasm. As such, entrapped neurons should be cytologically and architecturally typical (i.e. be of relatively uniform size, evenly-distributed, and lack binucleation). Rare entrapped neurons may be seen even in tumors described as "non-infiltrative" (i.e. WHO grade I). However, these should be few, and restricted to the periphery of the lesion. The second possibility is that the ganglion cells are participants in the neoplastic process, and are thus dysplastic. Ganglionic dyplasia is evidenced by cytologic pleomorphism (differing sizes and shapes), abnormal clustering, and binucleation. By immunohistochemistry, dysplastic ganglion cells have been reported to aberrantly express cytoplasmic CD34, and show a distinct membranous accentuation of synaptophysin immunoreactivity.
Gangliogliomas are rare neuroglial neoplasms that classically present with refractory epilepsy, and tend to lie in the temporal lobe neocortex. Intraventricular gangliogliomas are exceedingly rare (~ 9 reported). Radiographically, gangliogliomas often present as a cystic mass with an enhancing mural nodule; other tumors with similar presentations include pilocytic astrocytomas, hemangioblastomas, and pleomorphic xanthoastrocytomas. The tumor behavior, and thus the tumor grade, is determined by the glial component. Most are WHO grade I or II; examples of malignant transformation show anaplastic (WHO III) or glioblastomatous (WHO IV) components.
11-2-2011 Tumefactive demyelination
http://brain.oxfordjournals.org/content/131/7/1759.long
http://www.ajronline.org/content/182/1/195.full
The diagnosis in this case is tumefactive demyelination. Latin tumere means "to be puffed up". In cases of tumefactive demyelination, the patients frequently find themselves biopsied, as they often do not have a previous diagnosis of demyelinating disease, and radiographically present with enhancing (often ring) lesions with significant surrounding vasogenic edema resulting in variable mass effect. At this point, the radiologic differential diagnosis for ring-enhancing lesions needs to be considered:
1) Glioblastoma: Ring-enhancement reflects the central necrosis. The enhancing wall of often thick, undulating, and irregular
2) Metastatic tumors: Wall characteristics vary; suggestive findings include localization at the gray-white junction and multiplicity (a history of a malignancy elsewhere helps too, but is seldom provided)
3) Abscess: Ring-enhancement reflects central necroinflammatory debris. The enhancing wall is often thin and smooth (like an egg-shell). Also often at the gray white junction, a hotspot for lesions of hematogenous origin (see above)
4) Tumefactive demyelination: One helpful point is that the "ring" is often open. Classically, the ring opens in the direction of the overlying cortex. In this case, the ring didn't read the literature, and opens centrally.
5) Subacute infarct: Ring is irregular and nonspecific. May be present in a particular vascular territory or in a "watershed" area.
When dealing with macrophage-rich lesions in the CNS, the most basic point to address is the distinction between an infarct and demyelination. Relative sparing of axons traversing the lesion help distinguish the two; axons are largely preserved in demyelination, and are largely destroyed in infarcts. A neurofilament immunostain will highlight the presence or absence of traversing intralesional axons.
Tumefactive demyelination is a poorly-defined clinical entity. Middle-aged females are affected most often. Many patients do not have prior histories of demyelination. Approximately 70% will subsequently develop additional lesions sufficient for the diagnosis of multiple sclerosis.
Irregular, multilobulated astrocytes may be seen in the setting of demyelinating disorders, termed "Creutzfeldt astrocytes". As with most things in pathology, are neither sensitive nor specific.
9-3-2011: Angiocentric glioma (WHO I)
http://www.ncbi.nlm.nih.gov/pubmed/16215459
http://www.ncbi.nlm.nih.gov/pubmed/17598825
The diagnosis in this case is angiocentric glioma (WHO grade I), a rare, recently-described neuropathologic entity codified in the most recent WHO tumor of the central nervous system. This low-grade glial tumor primarily affects children and young adults, most often lying in the supratentorial compartment. Complete surgical resection is considered curative, hence the WHO grade I designation.
Neuropathologically, this is an important entity to be aware of; the unwary may overdiagnose as a higher-grade glioma, resulting in unnecessary chemotherapy and/or radiotherapy. The key to the diagnosis is the distinct perivascular accumulation of otherwise bland neoplastic cells with glial cytologic features. Areas of subpial accumulation may be seen as well. The tumor cells lie in bland neuropil, lending an infiltrative appearance. Immunohistochemically, the neoplastic cells variably express GFAP, and an epithelial membrane antigen (EMA) immunostain often shows perinuclear dot-like reactivity, indicative of ependymal differentiation. As in this case, GFAP and synaptophysin immunostains highlight the background neuropil.
8-7-2011: Primary melanocytic tumor, intermediate grade
http://www.ncbi.nlm.nih.gov/pubmed/10403296
The "Mystery immunostain" in this case was a melanoma cocktail; the reason the chromagen is red is to avoid confusion with a brown reaction product in cells with brown endogenous pigment; similar reasoning is used in utilizing a red chromagen in alpha-synuclein stains in looking for "Lewy bodies" in the pigmented neurons of the CNS (dorsal motor nucleus of the vagus nerve, locus coeruleus, and substantia nigra).
The diagnosis of primary CNS melanocytic neoplasms can only be entertained after the possibility of a cutaneous metastatic lesion has been excluded. Primary CNS melanocytic neoplasms are thought to arise from native leptomeningeal melanocytes, which may be found throughout the neuroaxis, but are most numerous in the medulla and rostral spinal cord. Thus, primary CNS melanocytic neoplasms tend to be found in similar locales... Histologically, primary melanocytic neplasms occupy a spectrum of histologic grade, from the rather indolent and well-differentiated melanocytoma, to the frankly malignant melanoma. Melanocytic tumors of intermediate grade occupy regions between, with intermediate MIB-1 indices and mitotic counts.
A particularly interesting (yet rare) phenomenon is the entity of "diffuse leptomeningeal melanosis", in which a diffuse leptomeningeal melanocytic proliferation (image) is accompanied by widespread cutaneous pigmented nevi (neurocutaneous melanosis); this condition predisposed affected patients to develop primary CNS malignant melanomas.
7-27-2011: Intravascular lymphoma (IVL), AKA "angiotropic large-cell lymphoma"
http://www.ncbi.nlm.nih.gov/pubmed/20569674
The low-power photomicrographs demonstrate ill-defined areas of parenchymal rarefaction and hemorrhage involving both the neocortex and subjacent white matter. High power examination reveals numerous foamy macrophages, reactive gliosis, and acutely necrotic neurons (not pictured), consistent with ischemic parenchymal necrosis. Several parenchymal and leptomeningeal vessels contain numerous highly atypical lymphoid cells, which stained strongly with a CD20 immunostain.
This was an interesting case, mostly because the diagnosis was so clearly unsuspected by all parties involved. Interestingly enough, I had was involved in the diagnosis of two case within a matter of months, so for a short time in my training, I felt that this was a relatively common disease.
The clinical and radiographic presentation is protean, and can mimic countless other CNS disorders. The diagnosis is rarely made antemortem. Cases with cutaneous involvement may be diagnosed by skin biopsy. Additionally, intravascular lymphoma tends to involve capillary-rich organs; involvement of lung and/or kidneys may be diagnosed by antemortem biopsy. "Angiotropic lymphomas", as the name implies, comprise a neoplastic proliferation of lymphocytes (most often large B-cell type) confined to the intravascular compartment. In a subset of cases, the neoplastic cells are EBV positive. Clinically, examples have been reported amongst a wide variety of age groups, sexes, and ethnicities.
7-1-2011: Neuronal Intranuclear Inclusion Disease (NIHID)
http://www.ncbi.nlm.nih.gov/pubmed/14719553
http://www.ncbi.nlm.nih.gov/pubmed/11305872
http://www.ncbi.nlm.nih.gov/pubmed/21411744
http://www.ncbi.nlm.nih.gov/pubmed/20299862
The gross findings in this case are limited to depigmentation of the substantia nigra and an organizing track (from deep brain stimulator). H&E stained sections showed innumerable prominent hyaline intranuclear inclusions in neurons throughout the neuroaxis (cerebral cortex, deep gray nuclei, brainstem, cerebellum, and spinal cord), some of which are shown on the representative photomicrographs. As pictured below, immunostains for ubiquitin showed consistent ubiquitin immunoreactivie intranuclear inclusions; a minority of inclusions were 1C2 (polyglutamine) immunoreactive.
These features are the defining neuropathologic features of neuronal intranuclear disease (NIHID). The clinical manifestations are quite protean and variable, manifesting as extrapyramidal motor abnormalites (i.e. Parkinsonism) and/or tremors in young patients and as progressive cognitive decline in older patients. The etiology of this condition is unclear, and wether this is a single disease entity or a group of etiologically-unrelated conditions is debatable. Other neuropathologic entities with intranuclear inclusions include the polyglutamine-repeat disorders (e.g. Huntington's disease spectrum) in which the inclusions are difficult to identify on routine sections and are consistently 1C2 immunoreactive (features not noted in this case). Cases with mutations in the ferritin light chain gene (i.e. ferritinopathy) also show prominent intranuclear inclusions which are reactive on iron stains. "Pre-mutation" carriers of Fragile-X syndrome may show intranuclear inclusions which are frequent in both neurons and glia in what is termed "Fragile-X dementia parkinsonism syndrome". Lastly, viral infections of the CNS and inclusions of no pathologic significance (Marinesco bodies) may be cause diagnostic confusion. The finding of occasional 1C2 raises the possibility that NIHID represents a polyglutamine-expansion disorder. However, in bona-fide cases of such cases, the inclusions are minute and consistently 1C2 immunoreactivity. While wild-type huntingtin protein and gene products associated with spinocerebellar ataxia (ataxins 2 and 3) have been noted in intranuclear inclusions, no CAG repeat expansion has been documented in susceptible genes. I realize that this discussion is much too cursory; for those with more interest, above are a few links to relevant articles.
5-26-2011: Langerhans Cell Histiocytosis (LCH), cranium
http://emedicine.medscape.com/article/1100579-overview
http://www.ncbi.nlm.nih.gov/pubmed/18647937
The MR demonstrates a homogenously-enhancing skull-based lesion of the left frontal bone, primarily effacing the normal marrow signal, with thickening and abnormal signal of both the adjacent soft tissue and subjacent meninges. H&E stained sections demonstrate a cellular lesion disrupting the normal bony architecture with the following components: 1) epitheloid cells with granular eosinophilic cytoplasm and medium-sized nuclei with distinct nuclear membranes, convoluted nuclear borders, frequent nuclear grooves, granular chromatin, and prominent nucleoli, 2) peripheral epitheloid histiocytes sans nuclear grooves, a subset of which coalesce into multinucleated giant cells, and 3) a brisk, eosinophil-enriched inflammatory infiltrate. Immunostains are pictured below. The histopathologic features and immunophenotype are consistent with Langerhans cell histiocytosis (LCH). Historically, these lesions were termed "eosinophilic granuloma", "Hans-Schuller-Christian disease", or "Letterer-Siwe syndrome", entities which differed primarily in clinical presentation, anatomic distribution, and prognosis. LCH typically occurs in children, most often as solitary osteolytic lesions of the skull or spine. Rare parenchymal lesions have been documented in the hypothalamus, infundibulum, optic chiasm, cerebral hemisphers, and/or choroid plexus. One key, "board relevant" point to remember is that this tumor has a classic ultrastructural presentation, namely the Birbeck granule, which is a pentalaminar rod-like structure with a bulbous terminus, giving it a "tennis racket" appearance. However, some examiners omit the bulbous end, expecting the examinee to recognize the pentalaminar rod as a Birbeck granule.
5-14-2011: Rosette forming glioneuronal tumor of the fourth ventricle
http://journals.lww.com/ajsp/Abstract/2002/05000/A_Rosette_Forming_Glioneuronal_Tumor_of_the_Fourth.4.aspx
This case is an example of an exceedingly rare tumor. The neuroimaging characteristics aren't particularly helpful (at least to a pathologist). The H&E sections show a tumor with a heterogenous histologic appearance; some areas closely resemble pilocytic astrocytomas, with oligodendroglia-like cells admixed with spindled cells with astrocytic features. Others show areas with dense calcification and Rosenthal fibers. Many rosettes, some of which are perivascular are noted, raising the possibility of an ependymoma. However, the fine, neuropil-like fibrillarity of the rosettes suggest neurocytic differentiation, hence the term "neurocytic rosettes". By immunohistochemistry, the tumor expressed GFAP (not shown) as well as neurocytic markers (MAP2, synaptophysin), thus the designation of the tumor as a glioneuronal neoplasm. Some have likened this tumor to an infratentorial DNET (see reference above). Along that line of reasoning, the vague lobularity of the tumor on neuroimaging is similar to that seen in supratentorial DNET. This tumor is a low-grade, WHO grade I neoplasm.
5-1-2011: Pick's disease (Pick's lobar degeneration)
http://www.ncbi.nlm.nih.gov/pubmed/16831037
http://emedicine.medscape.com/article/1135504-overview
The gross pathology of this case is characteristic; the severe gyral atrophy involving the frontal and andterior aspects of the temporal lobes, with the sparing of the precentral gyrus, and orbitofrontal gyri. Medial inspection demonstrates marked atrophy of the the anterior aspect of the cingulate gyrus, with sparing of the posterior half. The view showing the superior temporal gyrus reveals a "knife-edge gyrus", a pathology buzzword for Pick's disease. Pick's is characterized histologically by round, well-circumscribed, slightly basophilic neuronal cytoplasmic inclusions ("Pick bodies") seen in the neocortex and brainstem nuclei. Characteristically, the dentate gyrus shows inclusions in a high percentage of neurons. Thus, examination of a single section from the hippocampus which reveals such inclusions in the dentate gyrus leaves little room for diagnoses other than Pick's disease. Also characteristic is the fact that the tau in Pick's disease is exclusively 3-repeat tau (i.e. 3R tau). See below for the 3R and 4R tau distributions of selected neurodegenerative conditions. Phosphotau (AT8) is a screening antibody that detects nonspecific pathologic tau accumulation. Also, the Pick bodies are visible on the thioflavine S preparation, yet look distinctly different from typical Alzheimer-type pathology (i.e. tangles, plaques).
3R tau only: Pick's disease
4R tau only: Progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease
Both 3R/4R tau: Alzheimer disease
4-14-2011: Marburg disease (acute multiple sclerosis)
http://www.ncbi.nlm.nih.gov/pubmed/19779719
Marburg disease goes by many names, including acute multiple sclerosis (MS), fulminant MS, and Marburg type or variant MS. I prefer the term Marburg disease solely for the reason that it is listed as such in our "Bible" of neuropathology. There are several features in this case which justify the diagnosis; 1) the acute onset and fulminant course, 2) the predilection for involvement of the white matter in and around the deep gray structures (thalami, basal ganglia), corticospinal tracts, and the brainstem (which are grossly edematous and discolored), 3) the predominance of acute inflammation associated with demyelination (the lymphocytic component was sparse at best), and 4) foci of frank parenchymal necrosis associated with the demyelinating lesions, in this case present in the brainstem tegmentum, suggested grossly by the multifocal brown discoloration.
If a surgical biopsy was taken from a case such as this, and an appropriate clinical history not provided at the time of consultation, one could misinterpret the predominance of foamy histiocytes as representative of an infarct. The key is recognizing the presence of relative preservation of axons within the lesion, and the absence of obvious neuroglial necrosis.
Now to the "red herring". The LFB/PAS/H stain from the spinal cord sections shows symmetric, extremely well-demarcated areas of demyelination in the lateral and ventral corticospinal tracts, as well as the medullary pyramids, what we call "isomorphic lesions". These lesions are characterized by occasional axonal spheroids and scattered foamy macrophages; significant neutrophilic or lymphocytic infiltrates are absent. These features are consistent with descending Wallerian degeneration from a proximal (i.e. rostral) axonal injury, in this case from the fulminant demyelination in the internal capsule, medullary pyramids, and basis pontis. Wallerian degeneration can cause signal abnormalities on neuroimaging, thus explaining the finding of extensive signal abnormalities documented on antemortem neuroimaging in this case.
4-6-2011: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)
http://emedicine.medscape.com/article/946864-overview#showall
http://www.ncbi.nlm.nih.gov/pubmed/18990125
There's no way that a short summary can do this case justice. I'll try, though. The brain showed well-developed gyral atrophy characterized histologically by neuronal loss, parenchymal spongiosis coalescing to for parenchymal cysts, and pseudolaminar cavitation (see picture). Importantly, the changes parimarily affect the parietal and occipital lobes (characteristic of MELAS), and preferentially involve the crest of the gyri (opposite of an ischemic insult, again characteristic of MELAS). There is relative sparing of neurons in areas of otherwise markedly damaged brain parenchyma, again dissimilar to a nonspecific ischemic insult. Occasional ferruginated (i.e. mineralized) neurons are noted. The lateral ventricles are moderately dilated. The muscle biopsy shows well developed mitochondrial abnormalities in the form of "ragged-red fibers" (trichrome), COX-deficient fibers (combo stain, mitochondrial enzyme lost in many mitochondrial myopathies), SDH-hyperintense fibers (SDH, specific for mitochondria, retained in many mitochondrial myoapthies), and sarcoplasmic lipid accumulation (oil red O). Ultrastructurally, the muscle showed subsarcolemmal and intermyofibrillar mitochondrial accumulation. Unfortunately, paracrystalline inclusions of the type which may be seen in mitochondrial disorders were not identified.
3-28-2011: Melanotic neuroectodermal tumor of infancy
http://www.ncbi.nlm.nih.gov/pubmed/18558161
Characteristic of this entity, this tumor is a highly cellular neoplasm comprising irregular islands of highly primitive, "small round blue cells" in a cellular fibromyxoid stroma. Discrete foci of epitheloid cells containing neuromelanin, many of which form rounded "gland-like" structures, lie both within the highly cellular areas and the surrounding stroma. The small primitive "neuroblastic" areas contain rare, dysplastic ganglion-like cells (demonstrated in the bottom photomicrograph). Occasional mitoses and apoptoses are noted.
While the cell of origin of this exceedingly rare tumor is unknown, the histologic features suggest the tumor differentiates towards retina, hence the descriptive terms "melanotic progonoma" (progonoma = mass arising from displaced tissue) and "retinal anlage tumor" (anlage = primordium from which the organism develops).
Immunohistochemically, the small "neuroblastic" cells stain with markers for neuroepithelial derivation (e.g. synaptophysin, NSE, CD56), and the larger epitheloid cells stain with cytokeratin, HMB45, NSE, synaptophysin, and/or S100.
3-23-2011: Hemorrhagic necrosis with angioinvasive septate hyphae, suggestive of Aspergillosis spp, and remote temporal and occipital pole neocortical contusions
http://emedicine.medscape.com/article/960938-overview
Sections demonstrate septate hyphae with acute angle dichotomous branching in the midst of hemorrhagic parenchymal necrosis. In areas, intravascular organisms can be seen spreading through the walls of small parenchymal vessels, hence the hemorrhagic appearance. The GMS silver stain nicely highlights the organisms. One helpful feature to note was the fact that the foci of hemorrhagic necrosis lied predominantly at the gray-white junction, suggesting hematogenous dissemination. The history of immunosuppression (transplant), combined with the indication of significant pulmonary pathology, suggests an infectious etiology. For a review of diagnosis and classification of fungal elements by histopathology, refer to http://ajcp.ascpjournals.org/content/131/3/364.long (much thanks to Dr. Mark Cohen for the reference).
Also noted were ares of remote cortical destruction preferentially involving the crests of the gyri (manifested on the external images as thinning of the crests of the gyri and rusty discoloration) of the temporal and occipital poles, both ares of selective vulnerability to traumatic head injury.
3-11-2011: Secretory meningioma (WHO grade I)
This is a subtype of a benign (WHO grade I) meningioma referred to as a secretory meningioma. The characteristic features are the presence of so-called "pseudopsammoma bodies", which are rounded, eosinophilic spherules that appear to lie in the cytoplasm of meningothelial cells. By immunohistochemistry, these stain with carcinoembryonic antigen (CEA). The cells immediately surrounding the pseudopsammoma bodies stain with both CEA and epithelial markers (e.g. CAM 5.2). This particular subtype of meningioma does not infer a poor prognosis. There following subtypes, however, show a propensity for aggressive growth and recurrence.
WHO II: 1) Clear cell meningioma, 2) Chordoid meningioma
WHO III: 1) Papillary meningioma, 2) Rhabdoid meningioma
3-7-2011: Neurodegeneration with brain iron accumulation (NBIA).
http://emedicine.medscape.com/article/1150519-overview
This condition has historically been referred to by it's eponymous name, Hallervorden-Spatz disease. However, since Julius Hallervorden and Hugo Spatz were Nazis, and both admittedly performed their experiments on the brains of executed prisoners, this name has fallen out of favor. The en vogue name now is pantothenate kinase associated neurodegeneration, due to the recent discovery of PANK2 gene mutations. Key to the diagnosis is the recognition of the "rusty" discoloration of the globus pallidi and substantia nigra. Microscopically, the features of neuronal loss, variable spongiosis, frequent axonal spheroids (round, amorphous eosinophilic axonal swellings), and parenchymal iron accumulation are characteristic. Remember that mineralization of the basal ganglia is common, particularly in aged individuals, but the deposits comprise primarily calcium, and involve the parenchymal vasculature.
3-1-2011: Transtentorial herniation, secondary to large acute subdural hemorrhage.
Below is a short synopsis of each of the relevant findings, listed in order of appearance (top to bottom)
1) Flattening of the right cerebral hemisphere: In this case, the gyri are flattened on both the ipsilateral and contralateral cerebral hemispheres, indicating a relatively recent occurrence. In chronic subdural hemorrhages, the ipsilateral gyri are flattened (due to compression by the neomembrane), and the contralateral gyri are relatively uninvolved.
2) Notching of the medial temporal lobes secondary to bilateral transtentorial herniation. Notice the ill-defined discoloration of the inferior temporal and occipital lobe neocortex, indicating an acute infarct due to compression of both posterior cerebral arteries (PCA). Also remember the association with compression of the oculomotor nerves (CNIII), which lies medial to the uncus.
3) In the photo demonstrating the medial temporal lobe transtentorial herniation, notice the hemorrhagic discoloration in the right medial temporal lobe. This is known as a "herniation contusion", in which the contusion results from compression against a relatively immobile structure (in this case the tentorium). There is significant midline shift, and a right-sided subfalcine herniation.
4) Cross section of the midbrain demonstrating a "Kernohan's notch", which occurs secondary to displacement of the midbrain away from the space occupying lesion and compression of the cerebral peduncle against the tentorium, causing necrosis of the cerebral peduncle. The resulting hemiparesis is thus on the same side (ipsilateral) as the supratentorial lesion, a "false localizing" finding on neurologic examination.
5) Finally, a secondary brainstem hemorrhage, the so-called "Duret hemorrhage". These occur due to stretching and compromise of the pontine penetrating arteries, and subsequent hemorrhage located primarily in the pontine tegmentum. Incompatible with survival.
2-24-2011: Sturge-Weber syndrome (encephalotrigeminal angiomatosis)
http://emedicine.medscape.com/article/414222-overview
http://www.ncbi.nlm.nih.gov/pubmed/17980311
* Characteristic of Sturge-Weber syndrome is the leptomeningeal angiomatosis with dystrophic calcification of the leptomeningeal vasculature and superficial neocortex. The radiographic appearance, the so-called "tram-track" appearance of bilayered calcification of the leptomeninges and subjacent neocortex is highly characteristic. This patient had a large unilateral facial vascular malformation involving the trigeminal nerve distribution.
2-11-11: Leigh's syndrome (subacute necrotizing encephalopathy)
http://www.ncbi.nlm.nih.gov/pubmed/18805359
* Progressive neurodegenerative condition secondary to a variety of mitochondrial abnormalities. The key is the symmetry, involvement of the basal ganglia, medial thalami, and brainstem nuclei (particularly the colliculi and periaqueductal gray). The parenchymal damage with increased capillary density (the so-called "vasculonecrosis"), in the presence of preserved neurons, helps in the distinction with hypoxic-ischemic damage.
2-7-11: Colloid cyst of the third ventricle
http://www.ncbi.nlm.nih.gov/pubmed/11437572
* Additional pathologic diagnoses include cerebral edema (flattening of the gyri, narrowing of the sulci, and effacement of the gray-white junction), and a shunt track in the right parasagittal frontal lobe.
1-31-2-11: Dysembryoplastic neuroepithelial tumor (DNET)
http://www.ncbi.nlm.nih.gov/pubmed/19165515
* The key in this case is recognizing the characteristic findings of "floating neurons" in a background of small, oligodendroglia-like cells. The pathogenesis is a subject of much debate. Some consider this a hamartomatous process; others view this as the elusive "WHO grade I oligodendroglioma".
1-26-2011: Malignant melanoma metastatic to an atypical meningioma
http://www.ncbi.nlm.nih.gov/pubmed/20175961
1-20-2011: Amyloid myopathy
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1073950/
* I intentionally withheld the congo red from the case, as it would have given away the diagnosis. The Texas-red UV image was taken from the congo red stain. While inconvenient in that it requires access to a UV light source, Texas red is much more sensitive and dramatic for highlighting amyloid on congo red stains than either the red reaction product or apple-green birefringence. In addition, the crystal violet showed widespread, dramatic metachromasia in the amyloid. We look at crystal violet stains on a daily basis on the muscle biopsy service, but we seldom see reactivity as demonstrated by this case. On further investigation, we did find that the patient had a light-chain gammopathy, history that was not provided with the initial biopsy material.
1-16-2011: Subcortical laminar heterotopia
http://www.medlink.com/medlinkcontent.asp
1-11-2011: Copper beaten skull- indicative of increased intracranial pressure (in this case, hydrocephalus)
Intraventricular meningiomas are uncommon tumors, accounting for < 3% of intracranial meningiomas. The atrium of the lateral ventricles is the most common site; examples of 3rd and 4th ventricular tumors are much less common. The tumors tend to occur in younger patients (i.e. 2nd to 4th decades). However, younger patients may be affected, including infants (think of neurofibromatosis type II!). Atypical tumors are uncommon.
Regarding the differential for intraventricular tumors, remembering what cells normally occupy (or lie adjacent to) that location will cover pretty much everything...
Choroid plexus: Choroid plexus papilloma/carcinoma
Arachnoid rests (in choroid plexus tufts): Meningioma
Ependyma: Ependymoma, subependymoma
Subependymal glia: SEGA, gliomas
Neurons: Central neurocytoma, PNET
Other: Colloid cyst (foramen of Monro), teratoma, Cysticercosis
In this case, the finding of a banal, spindled, collagen-rich neoplasm is consistent with a fibrous meningioma. The solitary Psammoma body (and nearly the same number of meningothelial whorls) seals the deal. Immunohistochemical staining consisted of a sole Ki-67 immunostain. None others were needed. By the time that I realized that I had posted two meningiomas in a row, it was too late to go back. Such is life.
10-3-2012 Atypical meningioma (WHO grade II); Neurofibromatosis type II
The neuroimaging demonstrates multiple extra-axial homogenously-enhancing dural-based tumors. In addition, the sagittal section demonstrates an enhancing cerebellopontine angle tumor. Here is a more informative image (intentionally withheld to increase case difficulty).
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| Axial post-gadolinium T1 MRI --> Bilateral acoustic neuromas |
Components of Neurofibromatosis type II are as follows:
- Bilateral acoustic neuromas (schwannomas)
- Multiple meningiomas
- Meningioangiomatosis
- Spinal cord and peripheral nerve schwannomas
- Ependymomas
- Cataracts
Now, on to the specifics of this tumor. The tumor showed focal meningothelial whorls, consistent with meningioma. In addition, a finding that gets less attention in descriptions of meningioms are intranuclear pseudoinclusions, readily apparent in the second H&E image. Psammoma bodies may also be seen, but were rare and poorly-formed in this case. Meningiomas in patients with NF2 often behave in a more aggressive fashion, with an increased risk of tumor recurrence. Accordingly, this meningioma was designated as an atypical (WHO grade II) meningioma, a lesion with an increased risk of recurrence after resection. According to the WHO, one can arrive at a diagnosis of "atypical meningioma" by any of three routes
- Brain invasion - Meningioma infiltrating brain parenchyma. Of note, superficial spread into the neocortex along the Virchow-Robin space is not sufficient for brain invasion. In this case, the GFAP highlights islands of brain parenchyma amongst the meningioma, denoting brain invasion.
- Elevated mitotic index - 4 or more mitoses per 10 HPF
- Three or more of the following features: Prominent nucleoli, sheet-like growth, small cell change, spontaneous coagulative necrosis, and increased cellularity. Key-point--> Necrosis in a tumor subjected to pre-operative embolization does not count towards an atypical designation.
While not specifically indicated in the WHO criteria for an atypical meningioma, this tumor showed a greater degree of cytologic atypia than usually seen in a plain vanilla meningioma. In addition, the Ki-67 labeling index was 13.5%, also much greater than usual. I consider these worrisome features, and would communicate this information to the clinicians as "features worrisome for a more aggressive clinical course".
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| Small cell change |
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| Meningothelial whorl, mitotic figure, increased nuclear atypia |
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| Spontaneous geographic tumoral necrosis |
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| GFAP IHC - Brain invasion |
4-7-2012 "Black thyroid", Black discoloration of bone
http://www.jstage.jst.go.jp/article/internalmedicine/49/16/1835/_pdf
The finding of interest in this case was "charcoal black" discoloration of the otherwise unremarkable thyroid gland, as well as dark-brown discoloration of the inner aspect of the skull. This finding has been described in associated with long-term tetracycline (most often minocycline) ingestion. In this case, the previous minocycline therapy was most likely utilized for the treatment of bacterial endocarditis.
Besides bone and thyroid discoloration, there are reports of minocycline-induced black discoloration of teeth and, less often, of atherosclerotic plaques in large arteries. The etiology is uncertain. Proposed mechanisms include (but are not limited to) accumulation of oxidized minocycline breakdown products, inhibition of thyroid peroxidase, and interference with normal cellular degradation pathways (e.g. lysosomal). The clinical significance is uncertain, and likely minimal at best. Some authors report no clinical sequelae, others report hypothyroidism. Occurrences of neoplasia (papillary thyroid carcinoma, trabecular adenomas) in the setting of black thyroid are most likely incidental.
Histologic examination of the thyroid gland demonstrates accumulation of excess dark brown to black pigment in both the colloid and follicular epithelium. The thyroid epithelium is typically otherwise quiescent. Ultrastructurally, the accumulated material resembles lipofuscin; special stains typically positive in lipofuscin deposits (e.g. Fontana-Masson) are reportedly positive. Auto-fluorescence under fluorescent microscopy is also consistent with lipofuscin. Of note, lipofuscin normally accumulates in the thyroid glands (and diverse other organs) in aged individuals, just not to the extent of gross organs discoloration.
1-29-2012 Hydrophilic Polymer Emboli
http://www.ncbi.nlm.nih.gov/pubmed/19846823
http://www.ncbi.nlm.nih.gov/pubmed/20305613
This case was one in which I puzzled over the diagnosis for awhile before having that "Ah-ha!" moment. Infection with an endovascular parasitic organism was my prime consideration, but something just didn't seem right. Searching pubmed with descriptive terms yielded the correct diagnosis...
There are several reports of cases of embolization of the hydrophilic coating which ensheaths catheters used for endovascula procedures, in this case cerebral angiography. The purpose of the coating is to reduce friction and decrease the incidence of vasospasm. The two publications above (Mehta et al, Allen et al) describe several such cases. Unlike this case, in which the material was only seen in one sampled vessel and evidence of secondary damage was not seen, many of the reported cases show widespread embolization and subsequent tissue damage (e.g. ischemia, inflammation). Pathologically, the material is variably basophilic and lamellated, is non-refractile, does not polarize, and is often accompanied by a foreign-body type giant cell reaction.
12-27-2011 Chondroid chordoma
http://www.ncbi.nlm.nih.gov/pubmed/16604512
http://www.ncbi.nlm.nih.gov/pubmed/18055855
Chordomas are tumors which arise in areas associated with the embryonic notochord. The recognition of "conventional" chordomas is aided by the classic histologic finding of cords of "physaliferous (Greek--> "bubble bearing") cells". In examples such as this case, the majority of the tumor shows frank cartilaginous differentiation; only rare areas showed chordoid differentiation. The distinction between a well-differentiated chondrosarcoma and a chondroid chordoma requires immunohistochemistry. Owing to notochordal derivation, S100 is positive. Cytokeratin reactivity will distinguish a chordoma (+) from a chondroma/chondrosarcoma (-). Additional considerations include other neoplasms with chordoid features, notably a chordoid meningioma (will have areas of meningothelial differentiation).
A new immunohistochemical marker for the diagnosis of chordoma is currently being touted--> brachyury. A nuclear transcription factor identified by gene expression profiling, brachyury immunostains label the nuclei in a large percentage (90%) of chordomas, including chondroid chordomas. However, for practical purposes, as discussed above, a cytokeratin immunostain will suffice in the majority of cases.
The tumor behavior is characterized by local recurrence. Sarcomatous (de-differentiated) examples are rare. Of note, core biopsies of a suspected chordoid example is not indicated, as the tumors are relatively gelatinous and discohesive; tumor seeding of the biopsy tract or spread along traversed structures may be seen.
12-10-2011 Intraventricular ganglioglioma (WHO I)
http://www.ncbi.nlm.nih.gov/pubmed/19290468
http://www.ncbi.nlm.nih.gov/pubmed/18829326
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| GFAP IHC- highlights the spindled astrocytic cells |
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| NeuN IHC- highlights the nuclei of mature neurons ("ganglion cells") |
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| Neurofilament IHC- highlights both ganglionic cytoplasm and background axons |
Of note, ganglion-like cells within a glial population raises two possibilities: First, the ganglionic cells may represent entrapped pre-existing neurons in an infiltrative neoplasm. As such, entrapped neurons should be cytologically and architecturally typical (i.e. be of relatively uniform size, evenly-distributed, and lack binucleation). Rare entrapped neurons may be seen even in tumors described as "non-infiltrative" (i.e. WHO grade I). However, these should be few, and restricted to the periphery of the lesion. The second possibility is that the ganglion cells are participants in the neoplastic process, and are thus dysplastic. Ganglionic dyplasia is evidenced by cytologic pleomorphism (differing sizes and shapes), abnormal clustering, and binucleation. By immunohistochemistry, dysplastic ganglion cells have been reported to aberrantly express cytoplasmic CD34, and show a distinct membranous accentuation of synaptophysin immunoreactivity.
Gangliogliomas are rare neuroglial neoplasms that classically present with refractory epilepsy, and tend to lie in the temporal lobe neocortex. Intraventricular gangliogliomas are exceedingly rare (~ 9 reported). Radiographically, gangliogliomas often present as a cystic mass with an enhancing mural nodule; other tumors with similar presentations include pilocytic astrocytomas, hemangioblastomas, and pleomorphic xanthoastrocytomas. The tumor behavior, and thus the tumor grade, is determined by the glial component. Most are WHO grade I or II; examples of malignant transformation show anaplastic (WHO III) or glioblastomatous (WHO IV) components.
11-2-2011 Tumefactive demyelination
http://brain.oxfordjournals.org/content/131/7/1759.long
http://www.ajronline.org/content/182/1/195.full
The diagnosis in this case is tumefactive demyelination. Latin tumere means "to be puffed up". In cases of tumefactive demyelination, the patients frequently find themselves biopsied, as they often do not have a previous diagnosis of demyelinating disease, and radiographically present with enhancing (often ring) lesions with significant surrounding vasogenic edema resulting in variable mass effect. At this point, the radiologic differential diagnosis for ring-enhancing lesions needs to be considered:
1) Glioblastoma: Ring-enhancement reflects the central necrosis. The enhancing wall of often thick, undulating, and irregular
2) Metastatic tumors: Wall characteristics vary; suggestive findings include localization at the gray-white junction and multiplicity (a history of a malignancy elsewhere helps too, but is seldom provided)
3) Abscess: Ring-enhancement reflects central necroinflammatory debris. The enhancing wall is often thin and smooth (like an egg-shell). Also often at the gray white junction, a hotspot for lesions of hematogenous origin (see above)
4) Tumefactive demyelination: One helpful point is that the "ring" is often open. Classically, the ring opens in the direction of the overlying cortex. In this case, the ring didn't read the literature, and opens centrally.
5) Subacute infarct: Ring is irregular and nonspecific. May be present in a particular vascular territory or in a "watershed" area.
When dealing with macrophage-rich lesions in the CNS, the most basic point to address is the distinction between an infarct and demyelination. Relative sparing of axons traversing the lesion help distinguish the two; axons are largely preserved in demyelination, and are largely destroyed in infarcts. A neurofilament immunostain will highlight the presence or absence of traversing intralesional axons.
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| Neurofilament immunostain; abundant traversing axons - single central axonal spheroid |
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| CD68 immunostain - frequent macrophages, often perivascular |
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| GFAP immunostain - reactive astrocytes |
Irregular, multilobulated astrocytes may be seen in the setting of demyelinating disorders, termed "Creutzfeldt astrocytes". As with most things in pathology, are neither sensitive nor specific.
9-3-2011: Angiocentric glioma (WHO I)
http://www.ncbi.nlm.nih.gov/pubmed/16215459
http://www.ncbi.nlm.nih.gov/pubmed/17598825
The diagnosis in this case is angiocentric glioma (WHO grade I), a rare, recently-described neuropathologic entity codified in the most recent WHO tumor of the central nervous system. This low-grade glial tumor primarily affects children and young adults, most often lying in the supratentorial compartment. Complete surgical resection is considered curative, hence the WHO grade I designation.
Neuropathologically, this is an important entity to be aware of; the unwary may overdiagnose as a higher-grade glioma, resulting in unnecessary chemotherapy and/or radiotherapy. The key to the diagnosis is the distinct perivascular accumulation of otherwise bland neoplastic cells with glial cytologic features. Areas of subpial accumulation may be seen as well. The tumor cells lie in bland neuropil, lending an infiltrative appearance. Immunohistochemically, the neoplastic cells variably express GFAP, and an epithelial membrane antigen (EMA) immunostain often shows perinuclear dot-like reactivity, indicative of ependymal differentiation. As in this case, GFAP and synaptophysin immunostains highlight the background neuropil.
8-7-2011: Primary melanocytic tumor, intermediate grade
http://www.ncbi.nlm.nih.gov/pubmed/10403296
The "Mystery immunostain" in this case was a melanoma cocktail; the reason the chromagen is red is to avoid confusion with a brown reaction product in cells with brown endogenous pigment; similar reasoning is used in utilizing a red chromagen in alpha-synuclein stains in looking for "Lewy bodies" in the pigmented neurons of the CNS (dorsal motor nucleus of the vagus nerve, locus coeruleus, and substantia nigra).
The diagnosis of primary CNS melanocytic neoplasms can only be entertained after the possibility of a cutaneous metastatic lesion has been excluded. Primary CNS melanocytic neoplasms are thought to arise from native leptomeningeal melanocytes, which may be found throughout the neuroaxis, but are most numerous in the medulla and rostral spinal cord. Thus, primary CNS melanocytic neoplasms tend to be found in similar locales... Histologically, primary melanocytic neplasms occupy a spectrum of histologic grade, from the rather indolent and well-differentiated melanocytoma, to the frankly malignant melanoma. Melanocytic tumors of intermediate grade occupy regions between, with intermediate MIB-1 indices and mitotic counts.
A particularly interesting (yet rare) phenomenon is the entity of "diffuse leptomeningeal melanosis", in which a diffuse leptomeningeal melanocytic proliferation (image) is accompanied by widespread cutaneous pigmented nevi (neurocutaneous melanosis); this condition predisposed affected patients to develop primary CNS malignant melanomas.
7-27-2011: Intravascular lymphoma (IVL), AKA "angiotropic large-cell lymphoma"
http://www.ncbi.nlm.nih.gov/pubmed/20569674
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| Intravascular (angiotropic) large B-cell lymphoma |
This was an interesting case, mostly because the diagnosis was so clearly unsuspected by all parties involved. Interestingly enough, I had was involved in the diagnosis of two case within a matter of months, so for a short time in my training, I felt that this was a relatively common disease.
The clinical and radiographic presentation is protean, and can mimic countless other CNS disorders. The diagnosis is rarely made antemortem. Cases with cutaneous involvement may be diagnosed by skin biopsy. Additionally, intravascular lymphoma tends to involve capillary-rich organs; involvement of lung and/or kidneys may be diagnosed by antemortem biopsy. "Angiotropic lymphomas", as the name implies, comprise a neoplastic proliferation of lymphocytes (most often large B-cell type) confined to the intravascular compartment. In a subset of cases, the neoplastic cells are EBV positive. Clinically, examples have been reported amongst a wide variety of age groups, sexes, and ethnicities.
7-1-2011: Neuronal Intranuclear Inclusion Disease (NIHID)
http://www.ncbi.nlm.nih.gov/pubmed/14719553
http://www.ncbi.nlm.nih.gov/pubmed/11305872
http://www.ncbi.nlm.nih.gov/pubmed/21411744
http://www.ncbi.nlm.nih.gov/pubmed/20299862
The gross findings in this case are limited to depigmentation of the substantia nigra and an organizing track (from deep brain stimulator). H&E stained sections showed innumerable prominent hyaline intranuclear inclusions in neurons throughout the neuroaxis (cerebral cortex, deep gray nuclei, brainstem, cerebellum, and spinal cord), some of which are shown on the representative photomicrographs. As pictured below, immunostains for ubiquitin showed consistent ubiquitin immunoreactivie intranuclear inclusions; a minority of inclusions were 1C2 (polyglutamine) immunoreactive.
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| Frontal lobe; 1C2 (polyglutamine) immunostain |
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| Frontal lobe; ubiquitin immunostain |
These features are the defining neuropathologic features of neuronal intranuclear disease (NIHID). The clinical manifestations are quite protean and variable, manifesting as extrapyramidal motor abnormalites (i.e. Parkinsonism) and/or tremors in young patients and as progressive cognitive decline in older patients. The etiology of this condition is unclear, and wether this is a single disease entity or a group of etiologically-unrelated conditions is debatable. Other neuropathologic entities with intranuclear inclusions include the polyglutamine-repeat disorders (e.g. Huntington's disease spectrum) in which the inclusions are difficult to identify on routine sections and are consistently 1C2 immunoreactive (features not noted in this case). Cases with mutations in the ferritin light chain gene (i.e. ferritinopathy) also show prominent intranuclear inclusions which are reactive on iron stains. "Pre-mutation" carriers of Fragile-X syndrome may show intranuclear inclusions which are frequent in both neurons and glia in what is termed "Fragile-X dementia parkinsonism syndrome". Lastly, viral infections of the CNS and inclusions of no pathologic significance (Marinesco bodies) may be cause diagnostic confusion. The finding of occasional 1C2 raises the possibility that NIHID represents a polyglutamine-expansion disorder. However, in bona-fide cases of such cases, the inclusions are minute and consistently 1C2 immunoreactivity. While wild-type huntingtin protein and gene products associated with spinocerebellar ataxia (ataxins 2 and 3) have been noted in intranuclear inclusions, no CAG repeat expansion has been documented in susceptible genes. I realize that this discussion is much too cursory; for those with more interest, above are a few links to relevant articles.
5-26-2011: Langerhans Cell Histiocytosis (LCH), cranium
http://emedicine.medscape.com/article/1100579-overview
http://www.ncbi.nlm.nih.gov/pubmed/18647937
The MR demonstrates a homogenously-enhancing skull-based lesion of the left frontal bone, primarily effacing the normal marrow signal, with thickening and abnormal signal of both the adjacent soft tissue and subjacent meninges. H&E stained sections demonstrate a cellular lesion disrupting the normal bony architecture with the following components: 1) epitheloid cells with granular eosinophilic cytoplasm and medium-sized nuclei with distinct nuclear membranes, convoluted nuclear borders, frequent nuclear grooves, granular chromatin, and prominent nucleoli, 2) peripheral epitheloid histiocytes sans nuclear grooves, a subset of which coalesce into multinucleated giant cells, and 3) a brisk, eosinophil-enriched inflammatory infiltrate. Immunostains are pictured below. The histopathologic features and immunophenotype are consistent with Langerhans cell histiocytosis (LCH). Historically, these lesions were termed "eosinophilic granuloma", "Hans-Schuller-Christian disease", or "Letterer-Siwe syndrome", entities which differed primarily in clinical presentation, anatomic distribution, and prognosis. LCH typically occurs in children, most often as solitary osteolytic lesions of the skull or spine. Rare parenchymal lesions have been documented in the hypothalamus, infundibulum, optic chiasm, cerebral hemisphers, and/or choroid plexus. One key, "board relevant" point to remember is that this tumor has a classic ultrastructural presentation, namely the Birbeck granule, which is a pentalaminar rod-like structure with a bulbous terminus, giving it a "tennis racket" appearance. However, some examiners omit the bulbous end, expecting the examinee to recognize the pentalaminar rod as a Birbeck granule.
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| IHC; CD1a |
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| IHC; S100 |
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| IHC; CD68 |
5-14-2011: Rosette forming glioneuronal tumor of the fourth ventricle
http://journals.lww.com/ajsp/Abstract/2002/05000/A_Rosette_Forming_Glioneuronal_Tumor_of_the_Fourth.4.aspx
This case is an example of an exceedingly rare tumor. The neuroimaging characteristics aren't particularly helpful (at least to a pathologist). The H&E sections show a tumor with a heterogenous histologic appearance; some areas closely resemble pilocytic astrocytomas, with oligodendroglia-like cells admixed with spindled cells with astrocytic features. Others show areas with dense calcification and Rosenthal fibers. Many rosettes, some of which are perivascular are noted, raising the possibility of an ependymoma. However, the fine, neuropil-like fibrillarity of the rosettes suggest neurocytic differentiation, hence the term "neurocytic rosettes". By immunohistochemistry, the tumor expressed GFAP (not shown) as well as neurocytic markers (MAP2, synaptophysin), thus the designation of the tumor as a glioneuronal neoplasm. Some have likened this tumor to an infratentorial DNET (see reference above). Along that line of reasoning, the vague lobularity of the tumor on neuroimaging is similar to that seen in supratentorial DNET. This tumor is a low-grade, WHO grade I neoplasm.
5-1-2011: Pick's disease (Pick's lobar degeneration)
http://www.ncbi.nlm.nih.gov/pubmed/16831037
http://emedicine.medscape.com/article/1135504-overview
The gross pathology of this case is characteristic; the severe gyral atrophy involving the frontal and andterior aspects of the temporal lobes, with the sparing of the precentral gyrus, and orbitofrontal gyri. Medial inspection demonstrates marked atrophy of the the anterior aspect of the cingulate gyrus, with sparing of the posterior half. The view showing the superior temporal gyrus reveals a "knife-edge gyrus", a pathology buzzword for Pick's disease. Pick's is characterized histologically by round, well-circumscribed, slightly basophilic neuronal cytoplasmic inclusions ("Pick bodies") seen in the neocortex and brainstem nuclei. Characteristically, the dentate gyrus shows inclusions in a high percentage of neurons. Thus, examination of a single section from the hippocampus which reveals such inclusions in the dentate gyrus leaves little room for diagnoses other than Pick's disease. Also characteristic is the fact that the tau in Pick's disease is exclusively 3-repeat tau (i.e. 3R tau). See below for the 3R and 4R tau distributions of selected neurodegenerative conditions. Phosphotau (AT8) is a screening antibody that detects nonspecific pathologic tau accumulation. Also, the Pick bodies are visible on the thioflavine S preparation, yet look distinctly different from typical Alzheimer-type pathology (i.e. tangles, plaques).
3R tau only: Pick's disease
4R tau only: Progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease
Both 3R/4R tau: Alzheimer disease
4-14-2011: Marburg disease (acute multiple sclerosis)
http://www.ncbi.nlm.nih.gov/pubmed/19779719
Marburg disease goes by many names, including acute multiple sclerosis (MS), fulminant MS, and Marburg type or variant MS. I prefer the term Marburg disease solely for the reason that it is listed as such in our "Bible" of neuropathology. There are several features in this case which justify the diagnosis; 1) the acute onset and fulminant course, 2) the predilection for involvement of the white matter in and around the deep gray structures (thalami, basal ganglia), corticospinal tracts, and the brainstem (which are grossly edematous and discolored), 3) the predominance of acute inflammation associated with demyelination (the lymphocytic component was sparse at best), and 4) foci of frank parenchymal necrosis associated with the demyelinating lesions, in this case present in the brainstem tegmentum, suggested grossly by the multifocal brown discoloration.
If a surgical biopsy was taken from a case such as this, and an appropriate clinical history not provided at the time of consultation, one could misinterpret the predominance of foamy histiocytes as representative of an infarct. The key is recognizing the presence of relative preservation of axons within the lesion, and the absence of obvious neuroglial necrosis.
Now to the "red herring". The LFB/PAS/H stain from the spinal cord sections shows symmetric, extremely well-demarcated areas of demyelination in the lateral and ventral corticospinal tracts, as well as the medullary pyramids, what we call "isomorphic lesions". These lesions are characterized by occasional axonal spheroids and scattered foamy macrophages; significant neutrophilic or lymphocytic infiltrates are absent. These features are consistent with descending Wallerian degeneration from a proximal (i.e. rostral) axonal injury, in this case from the fulminant demyelination in the internal capsule, medullary pyramids, and basis pontis. Wallerian degeneration can cause signal abnormalities on neuroimaging, thus explaining the finding of extensive signal abnormalities documented on antemortem neuroimaging in this case.
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| Black arrows: axons (both myelinated and unmyelinated). Yellow arrows: macrophages (some containing blue myelin debris), Red arrow: reactive, "gemistocytic" astrocyte |
http://emedicine.medscape.com/article/946864-overview#showall
http://www.ncbi.nlm.nih.gov/pubmed/18990125
There's no way that a short summary can do this case justice. I'll try, though. The brain showed well-developed gyral atrophy characterized histologically by neuronal loss, parenchymal spongiosis coalescing to for parenchymal cysts, and pseudolaminar cavitation (see picture). Importantly, the changes parimarily affect the parietal and occipital lobes (characteristic of MELAS), and preferentially involve the crest of the gyri (opposite of an ischemic insult, again characteristic of MELAS). There is relative sparing of neurons in areas of otherwise markedly damaged brain parenchyma, again dissimilar to a nonspecific ischemic insult. Occasional ferruginated (i.e. mineralized) neurons are noted. The lateral ventricles are moderately dilated. The muscle biopsy shows well developed mitochondrial abnormalities in the form of "ragged-red fibers" (trichrome), COX-deficient fibers (combo stain, mitochondrial enzyme lost in many mitochondrial myopathies), SDH-hyperintense fibers (SDH, specific for mitochondria, retained in many mitochondrial myoapthies), and sarcoplasmic lipid accumulation (oil red O). Ultrastructurally, the muscle showed subsarcolemmal and intermyofibrillar mitochondrial accumulation. Unfortunately, paracrystalline inclusions of the type which may be seen in mitochondrial disorders were not identified.
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| Arrow= psuedolaminar cavitation, D= depth of sulcus, C= crest of gyrus |
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| Arrow= marked gyral atrophy |
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| Arrow= mineralized, "ferruginated" neurons - note how you can still see the neuritic processes extending from the soma |
http://www.ncbi.nlm.nih.gov/pubmed/18558161
Characteristic of this entity, this tumor is a highly cellular neoplasm comprising irregular islands of highly primitive, "small round blue cells" in a cellular fibromyxoid stroma. Discrete foci of epitheloid cells containing neuromelanin, many of which form rounded "gland-like" structures, lie both within the highly cellular areas and the surrounding stroma. The small primitive "neuroblastic" areas contain rare, dysplastic ganglion-like cells (demonstrated in the bottom photomicrograph). Occasional mitoses and apoptoses are noted.
While the cell of origin of this exceedingly rare tumor is unknown, the histologic features suggest the tumor differentiates towards retina, hence the descriptive terms "melanotic progonoma" (progonoma = mass arising from displaced tissue) and "retinal anlage tumor" (anlage = primordium from which the organism develops).
Immunohistochemically, the small "neuroblastic" cells stain with markers for neuroepithelial derivation (e.g. synaptophysin, NSE, CD56), and the larger epitheloid cells stain with cytokeratin, HMB45, NSE, synaptophysin, and/or S100.
3-23-2011: Hemorrhagic necrosis with angioinvasive septate hyphae, suggestive of Aspergillosis spp, and remote temporal and occipital pole neocortical contusions
http://emedicine.medscape.com/article/960938-overview
Sections demonstrate septate hyphae with acute angle dichotomous branching in the midst of hemorrhagic parenchymal necrosis. In areas, intravascular organisms can be seen spreading through the walls of small parenchymal vessels, hence the hemorrhagic appearance. The GMS silver stain nicely highlights the organisms. One helpful feature to note was the fact that the foci of hemorrhagic necrosis lied predominantly at the gray-white junction, suggesting hematogenous dissemination. The history of immunosuppression (transplant), combined with the indication of significant pulmonary pathology, suggests an infectious etiology. For a review of diagnosis and classification of fungal elements by histopathology, refer to http://ajcp.ascpjournals.org/content/131/3/364.long (much thanks to Dr. Mark Cohen for the reference).
Also noted were ares of remote cortical destruction preferentially involving the crests of the gyri (manifested on the external images as thinning of the crests of the gyri and rusty discoloration) of the temporal and occipital poles, both ares of selective vulnerability to traumatic head injury.
3-11-2011: Secretory meningioma (WHO grade I)
This is a subtype of a benign (WHO grade I) meningioma referred to as a secretory meningioma. The characteristic features are the presence of so-called "pseudopsammoma bodies", which are rounded, eosinophilic spherules that appear to lie in the cytoplasm of meningothelial cells. By immunohistochemistry, these stain with carcinoembryonic antigen (CEA). The cells immediately surrounding the pseudopsammoma bodies stain with both CEA and epithelial markers (e.g. CAM 5.2). This particular subtype of meningioma does not infer a poor prognosis. There following subtypes, however, show a propensity for aggressive growth and recurrence.
WHO II: 1) Clear cell meningioma, 2) Chordoid meningioma
WHO III: 1) Papillary meningioma, 2) Rhabdoid meningioma
3-7-2011: Neurodegeneration with brain iron accumulation (NBIA).
http://emedicine.medscape.com/article/1150519-overview
This condition has historically been referred to by it's eponymous name, Hallervorden-Spatz disease. However, since Julius Hallervorden and Hugo Spatz were Nazis, and both admittedly performed their experiments on the brains of executed prisoners, this name has fallen out of favor. The en vogue name now is pantothenate kinase associated neurodegeneration, due to the recent discovery of PANK2 gene mutations. Key to the diagnosis is the recognition of the "rusty" discoloration of the globus pallidi and substantia nigra. Microscopically, the features of neuronal loss, variable spongiosis, frequent axonal spheroids (round, amorphous eosinophilic axonal swellings), and parenchymal iron accumulation are characteristic. Remember that mineralization of the basal ganglia is common, particularly in aged individuals, but the deposits comprise primarily calcium, and involve the parenchymal vasculature.
3-1-2011: Transtentorial herniation, secondary to large acute subdural hemorrhage.
Below is a short synopsis of each of the relevant findings, listed in order of appearance (top to bottom)
1) Flattening of the right cerebral hemisphere: In this case, the gyri are flattened on both the ipsilateral and contralateral cerebral hemispheres, indicating a relatively recent occurrence. In chronic subdural hemorrhages, the ipsilateral gyri are flattened (due to compression by the neomembrane), and the contralateral gyri are relatively uninvolved.
2) Notching of the medial temporal lobes secondary to bilateral transtentorial herniation. Notice the ill-defined discoloration of the inferior temporal and occipital lobe neocortex, indicating an acute infarct due to compression of both posterior cerebral arteries (PCA). Also remember the association with compression of the oculomotor nerves (CNIII), which lies medial to the uncus.
3) In the photo demonstrating the medial temporal lobe transtentorial herniation, notice the hemorrhagic discoloration in the right medial temporal lobe. This is known as a "herniation contusion", in which the contusion results from compression against a relatively immobile structure (in this case the tentorium). There is significant midline shift, and a right-sided subfalcine herniation.
4) Cross section of the midbrain demonstrating a "Kernohan's notch", which occurs secondary to displacement of the midbrain away from the space occupying lesion and compression of the cerebral peduncle against the tentorium, causing necrosis of the cerebral peduncle. The resulting hemiparesis is thus on the same side (ipsilateral) as the supratentorial lesion, a "false localizing" finding on neurologic examination.
5) Finally, a secondary brainstem hemorrhage, the so-called "Duret hemorrhage". These occur due to stretching and compromise of the pontine penetrating arteries, and subsequent hemorrhage located primarily in the pontine tegmentum. Incompatible with survival.
2-24-2011: Sturge-Weber syndrome (encephalotrigeminal angiomatosis)
http://emedicine.medscape.com/article/414222-overview
http://www.ncbi.nlm.nih.gov/pubmed/17980311
* Characteristic of Sturge-Weber syndrome is the leptomeningeal angiomatosis with dystrophic calcification of the leptomeningeal vasculature and superficial neocortex. The radiographic appearance, the so-called "tram-track" appearance of bilayered calcification of the leptomeninges and subjacent neocortex is highly characteristic. This patient had a large unilateral facial vascular malformation involving the trigeminal nerve distribution.
2-11-11: Leigh's syndrome (subacute necrotizing encephalopathy)
http://www.ncbi.nlm.nih.gov/pubmed/18805359
* Progressive neurodegenerative condition secondary to a variety of mitochondrial abnormalities. The key is the symmetry, involvement of the basal ganglia, medial thalami, and brainstem nuclei (particularly the colliculi and periaqueductal gray). The parenchymal damage with increased capillary density (the so-called "vasculonecrosis"), in the presence of preserved neurons, helps in the distinction with hypoxic-ischemic damage.
2-7-11: Colloid cyst of the third ventricle
http://www.ncbi.nlm.nih.gov/pubmed/11437572
* Additional pathologic diagnoses include cerebral edema (flattening of the gyri, narrowing of the sulci, and effacement of the gray-white junction), and a shunt track in the right parasagittal frontal lobe.
1-31-2-11: Dysembryoplastic neuroepithelial tumor (DNET)
http://www.ncbi.nlm.nih.gov/pubmed/19165515
* The key in this case is recognizing the characteristic findings of "floating neurons" in a background of small, oligodendroglia-like cells. The pathogenesis is a subject of much debate. Some consider this a hamartomatous process; others view this as the elusive "WHO grade I oligodendroglioma".
1-26-2011: Malignant melanoma metastatic to an atypical meningioma
http://www.ncbi.nlm.nih.gov/pubmed/20175961
1-20-2011: Amyloid myopathy
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1073950/
1-16-2011: Subcortical laminar heterotopia
http://www.medlink.com/medlinkcontent.asp
1-11-2011: Copper beaten skull- indicative of increased intracranial pressure (in this case, hydrocephalus)
1-10-2011:
1) ALK1 Negative Anaplastic Large Cell Lymphoma
2) Splendore-Hoeppli phenomenon (eosinophilic perivascular material on frozen section)
1-4-2011: Hypothalamic Hamartoma
12-31-2010: Metastatic Merkel cell carcinoma
12-23-2010: Lhermitte-Duclos Disease
12-20-2010: Leptomeningeal Cryptococcal infection, HIV infection http://emedicine.medscape.com/article/1167389-overview
11-30-2010: Intrinsic Pontine Glioma (WHO II) http://www.childrenshospital.org/az/Site762/mainpageS762P0.html
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