Neuropathology Flashcards
This photomicrograph was taken from a tumor smear (squash preparation) prepared
intraoperatively from an enhancing extra-axial tumor. Which of the following is the most likely
diagnosis?
Answers:
A. Meningioma
B. Oligiodendroglioma
C. Renal cell carcinoma
D. Schwannoma
E. Epidermoid
Meningioma
Discussion:
Histologically meningiomas have a whorled, syncytial architecture composed of spindle to
polygonal cells with vacuolated cytoplasm and bland nuclei. They are positive for PAS, EMA,
vimentin and negative for cytokeratin (which differentiates them from renal cell carcinoma and
epidermoid) and GFAP (which differentiates them from oligodendrogliomas). Schwannomas are
S100 positive and biphasic, eliciting compact hypercellular Antoni A areas and myxoid hypocellular
Antoni B areas. Cells are narrow and elongated with wavy with tapered ends and interspersed with
collagen fibers. Verocay bodies, or nuclear palisading around a fibrillary process, can be seen in
cellular areas.
References:
Imlay SP1, Snider TE, Raab SS. Clear-cell meningioma: diagnosis by fine-needle aspiration
biopsy. Diagn Cytopathol. 1998 Feb;18(2):131-6.
Jain D1, Sharma MC, Sarkar C, Suri V, Garg A, Singh M, Sharma BS, Mahapatra AK. Clear cell
meningioma, an uncommon variant of meningioma: a clinicopathologic study of nine cases.J
Neurooncol. 2007 Feb;81(3):315-21. Epub 2006 Sep 6
The pathology seen in the silver-stained histologic specimen from the caudate nucleus shown was
most likely caused by which of the following processes?
Answers:
A. Mucor and Rhizopus species
B. Candida albicans
C. Aspergillus fumigatus
D. Coccidiomycosis
E. Cryptococcus neoformans
Aspergillus fumigatus
Discussion:
Aspergillus fumigatus is a fungus with septate hyphae that branch at a V-shaped (i.e. acute) 45
degree angle in a dichotomous fashion. Aspergillosis most commonly occurs in the settings of
chronic corticosteroid use or other immunosuppressed states. Hemorrhagic abscesses are typical
due to invasion of blood vessel walls, and secondary stroke leading to focal deficits. Mucor and
Rhizopus species are fungi with irregular nonseptate hyphae branching at wide angles > 90
degrees. They are characteristically associated with necrotic (not hemorrhagic) abscesses in
diabetic patients. Cryptococci are encapsulated eosinophilic fungi. They most commonly present in
the spore form and no hyphae are seen. They are best visualized with mucicarmine or India Ink
staining. Candida albicans is a fungus which typically presents as low-grade meningitis. It most
commonly occurs in neonates or post-operative adult neurosurgical patients. It is visualized with
KOH or PAS and pseudohyphae (i.e. non-septate hyphae) are seen. Coccidiomycosis is a fungal
infection identified by characteristic large spherules containing endospores on H&E stains.
References:
DeLone DR, Goldstein RA, Petermann G, et al. Disseminated aspergillosis involving the brain:
distribution and imaging characteristics. AJNR Am J Neuroradiol. 1999 Oct;20(9):1597-1604.
Prayson, Richard A; Goldblum, John R. Neuropathology: A Volume in the Foundation in Diagnostic
Pathology Series. ECL. 2005. Pg 303-304.
A 1-year-old boy is evaluated because of a cerebellopontine angle tumor. Histologic examination
shows predominantly small hyperchromatic primitive cells surrounding islands of large vacuolated
cells with eccentric nuclei and prominent nucleoli. The cells have a partial deletion of chromosome. These findings are most consistent with which of the following?
Answers:
A. Medulloblastoma
B. Immature teratoma
C. WHO grade III ependymomas
D. Choroid plexus papilloma (CPP)
E. Atypical teratoid/rhabdoid tumor (AT/RT)
Atypical teratoid/rhabdoid tumor (AT/RT)
Discussion:
All of these tumors occur in infants (children <1 year old) and can present with obstructive
hydrocephalus. All these tumors can occur in the posterior fossa; however, immature teratomas
tend to occur supratentorially, as do choroid plexus papilloma, making these options less likely. In
fact, choroid plexus papilloma, unlike most brain tumors, have a reverse epidemiological
occurrence: in adults, they tend to occur in the posterior fossa, but in children, they are almost
always supratentorial.
All these tumors can also hemorrhage, although this is much less likely to occur in ependymomas,
medulloblastomas and choroid plexus papillomas when compared to AR/RT.
Ependymomas in the posterior fossa tend to involve the ventricular space and/or the
cerebellopontine angle. Choroid plexus carcinomas involve the ventricular system as well, but they
more often occur in the lateral ventricles and trigone.
AT/RT is the most likely diagnosis for a child this young when compared to the other options.
AT/RT present in early childhood (median age less than 2-3 years), whereas medulloblastoma
typically occur in mid-childhood (median age 6 years).
Lastly, the genetic marker is exclusive to AT/RT. Rhabdoid cells are a hallmark of this tumor, but
they represent only a portion of the tumor and may not be detected on a biopsy sample.
Otherwise, this tumor is radiographically and histologically indistinguishable from medulloblastoma
or supratentorial primitive neuroectodermal tumor (PNET). In the 2016 WHO classification scheme,
AT/RT diagnosis requires confirmation of a genetic abnormality – loss of the SMARCB1 / INI tumor
suppressor gene on chromosome 22. The age and presentation are most likely to be AT/RT, and
with the genetic information provided in the question stem, AT/RT is the only option.
References:
Louis D, Perry A, Reifenberger G et al. The 2016 World Health Organization Classification of
Tumors of the Central Nervous System: a summary. Acta Neuropathologica. 2016;131 (6): 803.
Pubmed
Meyers SP, Khademian ZP, Biegel JA et al. Primary intracranial atypical teratoid/rhabdoid tumors
of infancy and childhood: MRI features and patient outcomes. AJNR Am J Neuroradiol. 2006;27
(5): 962-71. Pubmed citation
Phosphorylated tau protein is most likely to be found in a patient with which of the following
neurodegenerative disorders?
Answers:
A. Chronic traumatic encephalopathy
B. Amyotrophic lateral sclerosis
C. Friedereich ataxia
D. Parkinson disease
E. Picks disease
Chronic traumatic encephalopathy
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is thought to result
from mild repetitive head trauma. Symptoms have an insidious onset, most often years after the
initial injuries, with loss of normal attention, concentration and memory. This can progress, in some
cases in 2-3 years, to include motor symptoms such impaired gait, impaired, executive function,
lack of insight and poor judgement. Histologically, the presence of neurofibrillary tangles,
neurotangles, diffuse amlyoid plaques, and TAR DNA-binding protein 43 (TDP-43) binding protein
in subcortical and perivascular regions, often with reactive astrocytes and microglia is confirmation
of CTE.
Parkinson’s disease forms insoluble aggregates in the group of pathological disorders known as
synucleopathies. Parkinson’s disease will have cellular punctate cytoplasmic ovoid and round
inclusions as well as intracellular/extracellular Lewy bodies and neurotic plaques. In Pick’s
disease, the brain shows atrophy of frontal and temporal lobes, Pick bodies (tau-positive spherical
cytoplasmic neuronal inclusions, composed of straight filaments), and Pick cells (ballooned
neurons with dissolution of chromatin). The most characteristic finding in amyotrophic lateral
sclerosis (ALS) is loss of anterior horn motor neurons and gliosis in the spinal cord, brain stem and
motor cortex. Inclusion bodies may be seen on H&E stained sections, but distinctive ALS
inclusions are more easily identified with immunostaining. Findings consist of bunina bodies (round
to oval shaped eosinophilic granular cytoplasmic deposits of 3 - 6 μm seen most frequently within
motor neurons and often in chains), skein-like inclusions (intracytoplasmic thread-like structures
within neurons), and Spherical hyaline (Lewy-like) inclusions. Friedreich’s ataxia is the most
common autosomal recessive ataxia, and in the vast majority of patients, due to homozygous
expansion of a guanine–adenine–adenine (GAA) trinucleotide repeat in intron 1 of the frataxin
gene on chromosome 9q13. Dorsal root ganglia in Friedreich’s ataxia are smaller than normal and
may be difficult to recognize during dissection. Dorsal spinal roots are thin and gray. There is
increased ferritin immunoreactivity in satellite cells. In the normal state, ferritin reaction product
occurs in some but not all satellite cells, and the layer of this protein around neurons is relatively
thin. However, in Friedrich ataxia, this layer can be extremely thick and persists in residual
nodules.
References:
Omalu B, Bailes J, Hamilton RL, Kamboh MI, Hammers J, Case M, Fitzsimmons R. Emerging
histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes.
Neurosurgery. 2011 Jul;69(1):173-83
https://www.ncbi.nlm.nih.gov/pubmed/?term=emerging+histomorphologic+phenotypes+of+chronic
McKee AC, Cantu RC, Nowinski CJ et-al. Chronic traumatic encephalopathy in athletes:
progressive tauopathy after repetitive head injury. J. Neuropathol. Exp. Neurol. 2009;68 (7):
709-35.
Stern RA, Daneshvar DH, Baugh CM et-al. Clinical presentation of chronic traumatic
encephalopathy. Neurology. 2013;81 (13): 1122-9
The microscopic histopathologic findings from the resection of a left cerebellopontine angle mass
in a 46-year-old woman with ipsilateral hearing loss are shown. Which of the following is the most
likely diagnosis?
Answers:
A. Schwannoma
B. Endolymphatic sac tumor
C. Psammomatous meningioma
D. Cholesteatoma
E. Choroid plexus papilloma
Schwannoma
Discussion:
The clinical scenario and histopathology shown are most consistent with a vestibular
schwannoma. Schwannomas are S100 positive and biphasic, eliciting compact hypercellular
Antoni A areas and myxoid hypocellular Antoni B areas. Cells are narrow and elongated with wavy
with tapered ends and interspersed with collagen fibers. Verocay bodies, or nuclear palisading
around a eosinophic fibrillary process core, can be seen in cellular Antoni A areas.
References:
Vestibular Schwannomas Lessons for the Neurosurgeon Part II Molecular Biology and Histology,
Contemporary Neurosurgery: October 31, 2011 - Volume 33 - Issue 21 - p 4 doi:
10.1097/01.CNE.0000409881.15693.56
Renshaw, Andrew A. Surgical Pathology of the Nervous System and Its Coverings, 4th Edition.,
Advances in Anatomic Pathology: January 2003 - Volume 10 - Issue 1 - p 46-47.
The tumor excision specimen in the photomicrograph shown is from a 14-year-old boy who had a
third ventricle tumor. The most likely diagnosis is
Answers:
A. Germinoma
B. Embryonal carcinoma
C. Yolk sac tumors
D. Pineal cyst
E. Teratoma
Teratoma
Discussion:
Teratomas are comprised of cells originating from at least two and usually all three embryonic
layers: ectoderm, mesoderm and endoderm and would have elevated AFP and CEA. Yolk sac
tumors have Schiller-Duval bodies, which are pathognomonic. Schiller-Duval bodies consist of a
central blood vessel enveloped by germ cells within a space similarly lined by germ cells, which
resemble glomeruli. Hyaline droplets are present in all yolk sac tumors and stain positive for AFP,
PAS, and alpha-1-antitrypsin. Embryonal carcinoma is often found in mixed germ-cell tumors, and
AFP and b-HCG may be elevated. Germinomas have large, epithelioid cells with abundant PAS
positive cytoplasm coinciding with large, round nuclei as well as irregular and pleomorphic nuclei.
They may have prominent nests of lymphocytes with occasional granulomatous inflammation that
may obscure tumor cells. Loose fragments or single large pleomorphic and polygonal cells with
vacuolated cytoplasm and enlarged oval nuclei with prominent nucleoli can also be seen. They are
positive for PLAP, CD117 / c-kit, and OCT4. A pineal cyst would not show tumor cells or be positive
for PLAP or c-kit.
References:
Villano JL, Propp JM, Porter KR et-al. Malignant pineal germ-cell tumors: an analysis of cases from
three tumor registries. Neuro-oncology. 2008;10 (2): 121-30. https://www.ncbi.nlm.nih.gov/pubmed
/18287340
Hattab EM, Tu PH, Wilson JD, Cheng L. OCT4 immunohistochemistry is superior to placental
alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg
Pathol. 2005 Mar;29(3):368-71.
https://www.ncbi.nlm.nih.gov/pubmed/15725806
Perivascular pseudorosettes are a diagnostic feature of which of the following tumors?
Answers:
A. Retinoblastoma
B. Ependymomas
C. Neuroblastoma
D. Medulloblastomas
E. Primitive neuroectodermal tumors
Ependymomas
Discussion:
Homer Wright rosettes are typically seen in neuroblastomas, medulloblastoma, and primitive
neuroectodermal tumors (PNETs). They consist of halos of tumor cells surrounding a central
region containing neuropil (hence its association with tumors of neuronal origin). FlexnerWintersteiner rosettes are characteristic of retinoblastomas. They consist of tumor cells
surrounding a central lumen that contains cytoplasmic extensions from the tumor cells. If one looks
at the tumor cells under electron microscopy, they have features of primitive photoreceptor cells.
Perivascular rosettes consist of tumor cells collected around a blood vessel and are termed
pseudorosettes because the central structure is not part of the tumor. These rosettes are common
in ependymomas.
References:
F.J. Wippold and A. Perry Neuropathology for the Neuroradiologist: Rosettes and Pseudorosettes.
American Journal of Neuroradiology March 2006, 27 (3) 488-492.
Prayson, Richard A; Goldblum, John R. Neuropathology: A Volume in the Foundation in Diagnostic
Pathology Series. ECL. 2005. Pg 468-469
A patient with posterior interosseous nerve syndrome is able to extend the wrist because of
sparing of innervation to which of the following muscles?
Answers:
A. Extensor carpi radialis longus
B. Pronator
C. Extensor carpi ulnaris
D. Extensor carpi radialis brevis
E. Brachioradialis
Extensor carpi radialis longus
Discussion:
The posterior interosseous nerve is a distal branch of the radial nerve that provides motor
innervation to the supinator, extensor carpi radialis brevis, extensor digitorum communis, extensor
digiti minimi, extensor carpi ulnaris, abductor pollicis, extensor pollicis brevis, extensor pollicis
longus, and extensor indicis. The classic finding is preserved wrist extension as the extensor carpi
radialis longus branches proximal to the leading edge of the supinator the most common
entrapment point of the posterior interosseous nerve. The pronator is a motor branch of the
median nerve that provides distal forearm innervation of the pronator muscle. The brachioradialis
is innervated by the radial nerve and provides elbow flexion, innervation occurs prior to the leading
edge of the supinator and is spared in PIN syndrome.
References:
Posterior Interosseous Nerve Syndrome Rachel Wheeler, Alexei DeCastro 1 In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. 2020 Oct 27. PMID: 31082090
Strohl AB, Zelouf DS. Ulnar Tunnel Syndrome, Radial Tunnel Syndrome, Anterior Interosseous
Nerve Syndrome, and Pronator Syndrome. J Am Acad Orthop Surg. 2017 Jan;25(1):e1-e10. doi:
10.5435/JAAOS-D-16-00010. PMID: 27902538.
Dang AC, Rodner CM. Unusual compression neuropathies of the forearm, part I: radial nerve. J
Hand Surg Am. 2009 Dec;34(10):1906-14. doi: 10.1016/j.jhsa.2009.10.016. PMID: 19969199.
Which of the following tumors is most likely to be associated with an abnormality in chromosome 17?
Answers:
A. Neurofibromatosis type 1
B. Von Hippel Lindau
C. Neurofibromatosis type 2
D. Cowden Syndrome
E. Tuberous Sclerosis
Neurofibromatosis type 1
Discussion:
The NF1 gene has been mapped to chromosome 17q11.2 and encodes the tumor-suppressor
protein neurofibromin. The NF2 gene, which is felt to be a tumor-suppressor gene, is located at
chromosome 22q12, and encodes a protein called merlin (or schwannomin). The Von Hippel
Lindau VHL gene has been mapped to chromosome 3p25-p26. Tuberous Sclerosis has been
linked to two different loci: TS complex-1 (TSC1), located on chromosome 9q34 which encodes the
protein hamartin, and TSC2 that has been mapped to chromosome 16p13.3 and encodes the
protein tuberin. The Cowden Syndrome mutation often occurs in the PTEN gene on chromosome
10.
References:
Pan E, Prados MD. Familial Tumors Syndromes of the Central Nervous system. In: Kufe DW,
Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton
(ON): BC Decker; 2003. Available from: https://www.ncbi.nlm.nih.gov/books/NBK13658/
Grill Jacques, Owens Cormac. Chapter 99 - Central nervous system tumors. Editor(s): Olivier
Dulac, Maryse Lassonde, Harvey B. Sarnat, Handbook of Clinical Neurology, Elsevier, Volume
112, 2013, Pages 931-958, ISSN 0072-9752, ISBN 9780444529107, https://doi.org/10.1016
/B978-0-444-52910-7.00015-5.
(https://www.sciencedirect.com/science/article/pii/B9780444529107000155)
Which of the following immunohistochemical markers is most accurate in diagnosing a central
neurocytoma?
Answers:
A. Synaptophysin
B. S100
C. GFAP
D. EMA
E. Vimentin
Synaptophysin
Discussion:
Strong staining for the neuronal marker synaptophysin, as well as for neuron-specific enolase, is
characteristic of central neurocytoma. Glial tumors are usually vimentin and GFAP positive.
Meningiomas, on the other hand, are usually positive for vimentin and EMA, but negative for
GFAP. S100 stains for neural crest cell derived tumors, including schwannomas, melanocytes,
chondrocytes, etc.
References:
Li Y, et al. Pathologic features and clinical outcome of central neurocytoma: analysis of 15 cases.
Chin J Cancer Res 2012 Dec;24(4):284-90. https://www.ncbi.nlm.nih.gov/pubmed/23358787
Louis DN, et al. The 2016 World Health Organization Classification of Tumors of the Central
Nervous System: a summary. Acta Neuropathol. 2016 Jun; 131(6):803-20.
https://www.ncbi.nlm.nih.gov/pubmed/27157931
An 18-year-old woman has a cerebellar tumor. H & E stained tissue from the tumor is shown in the
photomicrographs. Which of the following is the most likely diagnosis?
Answers:
A. Pilocytic astrocytoma
B. Meningioma
C. Medulloblastoma
D. Schwannoma
E. Hemangioblastoma
Pilocytic astrocytoma
Discussion:
The photomicrograph demonstrates a pilocytic astrocytoma, with evidence of a proliferation of
dense fibrillary, piloid cells arranged in fascicles. Rosenthal fibers, brightly eosinophilic masses
intermixed with the tumor cells, are present. This is a characteristic arrangement seen in pilocytic
astrocytomas. Pilocytic astrocytomas may also present in a biphasic pattern with alternating areas
of compact, piloid cells and areas of microcystic or loose appearance of the tumor. Rosenthal
fibers tend to be more prominent in the compact piloid areas. Although they are typically seen in
pilocytic astrocytoma, these intracytoplasmic, fibrillary structures may also be seen in chronic
reactive gliosis in particular in the hypothalamus, cerebellum and spinal cord. Histologically
meningiomas have a whorled, syncytial architecture composed of spindle to polygonal cells with
vacuolated cytoplasm and bland nuclei. They are positive for PAS, EMA, vimentin and negative for
cytokeratin and GFAP. Schwannomas are S100 positive and biphasic, eliciting compact
hypercellular Antoni A areas and myxoid hypocellular Antoni B areas. Cells are narrow and
elongated with wavy with tapered ends and interspersed with collagen fibers. Verocay bodies, or
nuclear palisading around a fibrillary process, can be seen in cellular areas.
References:
Fernandez C, Figarella-Branger D, Girard N, Bouvier-Labit C, Gouvernet J, Paz Paredes A, Lena
G. Pilocytic astrocytomas in children: prognostic factors–a retrospective study of 80 cases.
Neurosurgery. 2003 Sep;53(3):544-53; discussion 554-5.
Collins VP, Jones DT, Giannini C. Pilocytic astrocytoma: pathology, molecular mechanisms and
markers. Acta Neuropathol. 2015 Jun;129(6):775-88. doi: 10.1007/s00401-015-1410-7. Epub 2015
Mar 20. PMID: 25792358; PMCID: PMC4436848.
Which of the following is the most common cause of brain abscess in adults?
Answers:
A. S. milleri
B. N. meningitides
C. S. pneumoniae
D. S. aureus
E. H. influenza
S. aureus
Discussion:
Gram positive cocci dominate as the pathogens for brain abscesses. The S. Milleri group,
including S. constellatus, S. intermedius, and S. anginosis, is the most common cause of cerebral
abscess, 50-70%, although cerebral abscesses are frequently polymicrobial. Staphylococci
account for 10-30%. S. aureus is the most common cause of spinal abscesses. Although S.
pneumoniae is a common cause of meningitis, it rarely causes brain abscess. S. pneumoniae, N.
meningitides, and H. influenzae are common causes of meningitis in the pediatric population. N.
meningitides is also common in adult meningitis.
References:
Smith SJ, Ughratdar I, MacArthur DC. Never go to sleep on undrained pus: a retrospective review
of surgery for intraparenchymal cerebral abscess. Br J Neurosurg. 2009 Aug;23(4):412-7. PubMed
PMID: 19637013.
Kowlessar PI, O’Connell NH, Mitchell RD, Elliott S, Elliott TS. Management of patients with
Streptococcus milleri brain abscesses. J Infect. 2006 Jun;52(6):443-50. Epub 2005 Oct 18.
PubMed PMID: 16239034.
Christopher J. Harrison, in Principles and Practice of Pediatric Infectious Diseases (Fifth Edition),
2018.
