Transcript Case Study 51 - University of Pittsburgh

Case Study 51
Jennifer Picarsic, M.D.
PGY-4 Resident
Question 1
Received in consultation are slides from a 5 month old
girl with year history of intra-uterine hydrocephalus,
large head at birth and left zygomatic mass
Describe the radiographic appearance.
Head ultrasound at birth
Head ultrasound at 1 month
MRI: T1 Coronal without contrast
MRI: Horizontal with contrast
CT- Zygomatic mass
Head ultrasound at birth
Dilated lateral
ventricles
Head ultrasound at 1 month
Increased size
lateral ventricles
Head Ultrasound- Prominent hydrocephalous, 2 intraventricular masses.
5.4 cm
3.0 cm
w/o C: Intraventricular mass centered at level of 4th ventricle, extends into 3rd; and measures
5.4 x 4.3 x 3.6 cm. Cerebellar tonsillar displacement downward filling the foramen magnum.
Second intraventricular mass is in lateral ventricle near foramen of Monroe, measuring 3 x 3 x
2.3 cm and is likely obstructing at this point, given the marked enlargement of the left lateral
ventricle; with slit like right lateral ventricle 2/2 to mass effect.
Third mass: left temporal lobe, with soft tissue extention.
w/C
Mild heterogeneous enhancement on post
contrast images.
T2 (not shown) demonstrated increased signal
intensity around the occipital horn of the left
lateral ventricle—suggesting transepedymal flow
CT- Zygomatic mass
CT imaging shows of a left temporal mass
lesion with bone and soft tissue
component with soft tissue extension as well
as extension through calvarium. measuring,
2.5 cm
Question 2
What would be your radiographic differential diagnosis in
this 5 month old child?
Answer
A high grade lesion would be highest on the differential
given the temporal mass eroding through calvarium and
extending into soft tissue. There is a multifocal tumor with
possible intraventricular spread, with primary involvement
of the posterior fossa and obstructive hydrocephalus.
PNET/Medulloblastoma with bony metastasis to left
temporal region (decreased intensity on T1)
Atypical teratoid/rhabdoid tumor
Choroid plexus carcinoma (should have hyperintense,
contrast enhancing lesions)
Ependymoma; ?Other high grade gliomas
Question 3
Describe the microscopic findings in a representative H&E
sections of the subcutaneous temporal area tumor.
Part 1: Click here to view slide of Zygomatic mass that
was biopsied
Part 2: Click here to view slide from tissue came out with
the needle of decompression of hydrocephalus
Answer
Part 1: Sheets of malignant appearing cells with a jumbled
architecture, no real pattern, and no definite rosette formation. The
cells have moderate eosinophilic cytoplasm with an occasional cell
showing a more pink eccentrically placed cytoplasm, leaving a
suggestion for rhabdoid morphology. The nuclei are pleomorphic with
anaplasia, very prominent large nucleoli and irregular nuclear
contours. Mitotic figures are abundant and occasional atypical
mitoses are present. There are small areas of necrosis, apoptotic
bodies, and a mild lymphocytic infiltrate.
Part 2: Tissue that came out with the needle for decompression of
hydrocephalus sampled normal choroid plexus. There was a very
minute fragment of malignant appearing cells of to one edge. It was
felt that the intraventricular masses represent the same malignancy
as part 1, but were just were not specifically sampled.
Question 4
What immunohistochemical stains would help you in
making your diagnosis?
Answer (IHC)
Atypical teratoid/rhabdoid tumor
Epithelial, neuronal, and mesenchymal markers should all be positive
— EMA, CAM5.2, GFAP, Synaptophysin, NF, vimentin, SMA, myogenin
Medulloblastoma/supratentorial P-NET
Synaptophysin, NSE, GFAP, vimentin, S100
— Medullomyoblastoma-myoglobulin, desmin positivity
Choroid Plexus Carcinoma
EMA, vimentin, cytokeratin, GFAP, p53, transthyretin, potassium channel
Kir7.1 (mbr)
Ependymoma (anaplastic)
EMA (dot like), GFAP
Lymphoma (large cell or blastic)
LCA, CD3, CD20, PAX5, Tdt
synaptophysin
GFAP
SMA
Myogenin
CAM 5.2
EMA
Ki-67- 50%
IHC Stains
Synaptophysin - Rare tumor cells show cytoplasmic immunoreactivity
GFAP- Tumor is negative
Smooth muscle actin - Patchy light to moderate staining
Myogenin - Scattered positive cells
Desmin (not shown) - Tumor is negative
CAM 5.2 – Patchy tumor positive staining
EMA – Patchy tumor positive staining
LCA (not shown) - Positive mostly in small infiltrating lymphocytes
CD3 (not shown) - Positive mostly in small infiltrating lymphocytes
CD20 (not shown) - Negative
PAX5 (not shown) - Negative
CD79a (not shown) - Rare positive cells; most of tumor shows equivocal
light cytoplasmic blush
Tdt (not shown) - Negative
Ki67 - Tumor proliferative index is 50%.
Question 5
What additional IHC and molecular tests would help
differentiate the two embryonal tumors?
INI-1 tumor
negative;
positive internal
control
Transthyretin – nonspecific stain of serum
Positive in Choroid plexus Carcinomas
Answer
 INI-1/ BAF47 -Tumor cells are negative; positive internal controls with
endothelial cells/lymphocytes positive
 Normally expressed in normal tissue without mutation/deletion
 The loss of nuclear staining is found in AT/RT, as well as RT of the
kidney. The relative specificity is declining as more tumors show loss
of INI-1
 Molecular
 AT/RT – monosomy deletion/mutations of 22p11.2 (INI1/hSNF5) gene
(75%) (exons 5 and 9 hot spots) or less frequently a homozygous
deletion (20%)
 May be a part of the rhabdoid tumor predisposition syndrome
 Medulloblastoma – nonspecific, +/- MYC/MYCN oncogene
amplification (worst survival), also gains in 6q, 17q, and 6q loss (best
survival)
What is your final diagnosis
FINAL
 Part 1: SUBCUTANEOUS TUMOR, EXCISION:
ATYPICAL TERATOID/RHABDOID TUMOR, WHO
GRADE 4.
 Part 2: INTRAVENTRICULAR TUMOR, BIOPSY
CHOROID PLEXUS WITH MINUTE FRAGMENT OF
ATYPICAL TERATOID/RHABDOID TUMOR
Loss of INI-1
 The complete loss of INI-1/BAF47 protein is thought to be specific finding
for Atypical Teratoid / Rhabdoid Tumors of the CNS and kidney, which
was recognized to have biallelic deletion/mutations at the 22q11.2 locus
of the INI-1 gene (also known as SMARCB1, hSNF5, or BAF47)
 Homozygous deletion or heterozygous deletion with a “second-hit”
mutation of this tumor suppressor gene
 The gene is important in the SWItch/Sucrose(SNF) ATP-dependent
chromatin remodeling complex
 Chromatin restricts the access to transcription factor DNA by tightly bound
histones and other proteins
 Protein groups such as the polycomb and trithorax protein groups act to
remodel chromatin, thus altering the accessibility of DNA to factors
required for gene transcription
 The SWI/SNF complex controlled by the INI-1 gene allows chromatin
remodeling for transcriptional regulation of specific genes to ensure
correct cell identity during development and differentiation.
Loss of INI-1 insights into
histogenesis
 Recently in renal rhabdoid tumors, neuronal and neural crest
development genes are differentially down-regulated (PTN,
DOCK4,PTPRK, SPOCK1), as compared to other pediatric renal
tumors
 The histogenesis is now thought to be an early progenitor cell at a
critical developmental window in which loss of INI-1 leads to arrest
or repression of normal neural development, dysregulation of the
thithorax/polycomb groups, and silencing of cell cycle dependent
kinase inhibitors to allow uncontrolled growth
 This may help explain why these tumors shows lineage of
neuronal, epithelial, and mesenchymal origins.
Not as specific as we thought

While the complete loss of INI-1 was thought to be a defining genetic feature of the
AT/RT, we are now seeing that it is not as specific as once thought

Other tumors now show loss of INI-1 by IHC, without the classic histologic rhabdoid
features of AT/RT, including cases with the diagnosis of Medulloblastoma/PNET, with
molecular confirmation of 22q11.2 loss.1

Previously diagnosed choroid plexus carcinomas have been re-classified as AT/RT
based on loss of INI-1 staining, though there is still some controversy around this topic. 2

Rhabdoid glioblastomas have demonstrated both areas of complete INI-1 loss and other
areas with INI-1 retention, compared to epithelioid glioblastomas which complete
retention.3

A newly proposed neuroectodermal tumor called cribriform neuroepithelial tumor
(CRINET), was described in 2 children with contrast enhancing tumors of the 3 rd/4th
ventricles that had cribriform strands and trabeculae, without rhabdoid features but
showed loss of the INI-1 protein, with one demonstrating a stop codon mutation in
22q11.2 locus.4 There was a lower proliferation index and these children are alive after 5
years.

Furthermore, syndromic schwannomatosis, including familial schwannomatosis, sporadic
schwannomatosis and those in NF2 schawannomas show a heterogenous/mosaic
pattern of INI-1 loss (ie. Mixture of cells both with loss of INI-1 adjacent to others with
retention).5
References
1. Haberler et al. Am J Surg Pathol. 2006. Nov;30(11):14628.
2. Judkins, Hamilton et al. J Neuropathol Exp Neurol. 2005
May;64(5):391-7.
3. Kleinschmidt-DeMasters et al. Am J Surg Pathol. 2010
Mar;34(3):341-54.
4. Hasselblatt et al. J Neuropathol Exp Neurol.
2009;68(12):1249-1255.
5. Patil et al. Brain Pathol. 2008 Oct;18(4):517-9.