Atypical Teratoid/Rhabdoid Tumor

Definition

Clinical Features

• Highly aggressive
• Usually infancy and early childhood:1,2
  • at diagnosis:
    • >90% aged <5 years (mean 20 months)
    • ≈33% have CSF dissemination

Pathogenesis

• A unified entity supported by cytogenetic and molecular genetic observations3,4
• Appears that INI 1 gene functions as a tumor suppressor gene in development3,4
• Suggested progenitors include:
  • mesenchymal cells
  • neuroectomesenchymal cells
  • meningeal cells
  • stem cells
  • germ cells
• None has ever contained elements of:
  • germinoma
  • embryonal carcinoma
  • yolk sac tumor
  • choriocarcinoma
  • syncytiotrophoblastic giant cells
  • organoid structures (e.g. miniature gut- or bronchus-like formations) found in many bona fide teratomas
• Only small minority arise along midline suprasellar–pineal axis in which 90% of intracranial germ cell tumors originate

Gross Pathology

• ≈50% cerebellum or cerebellopontine angle
  • often with contiguous brainstem involvement
• ≈40% supratentorial (cerebral or suprasellar)
• ≈5% pineal region
• ≈2% intraspinal

Histopathology

• Potentially complex1,2
• Minority consist solely of rhabdoid cells
• Rhabdoid cells classically:
  • distinct cell borders
  • large and vesicular nuclei
  • macronucleoli
  • globose paranuclear cytoplasmic inclusions of hyalin appearance
• Rhabdoid cells may be only sparsely represented among nonrhabdoid tumor cells
• Nonrhabdoid tumor cells:
  • large cells
  • include variably spindled, polygonal and bizarre multinucleated cells
  • uniformly dense and eosinophilic finely granular vacuolated wispy or water-clear cytoplasm (Fig. 1
    

    Fig. 1: Atypical teratoid/rhabdoid tumor. Neoplasms of this family typically contain at least some cells of large, rhabdoid phenotype.

    )
  • in nests or sheets
  • sometimes:
    • traversed by bands of hyalinized collagen
    • myxoid change and chordoid growth pattern
• Adjectival ‘teratoid’ reflects common presence of varied neoplastic tissue components: (Fig. 2
  

  Fig. 2: Atypical teratoid/rhabdoid tumor. This example harbors, at right, small cell elements of primitive neuroepithelial appearance and a differentiated glandular structure, at left, embedded in a neoplastic component of mesenchymal aspect.

  )
  • small cell elements of embryonal appearance indistinguishable from those that typify medulloblastoma/PNET:
    • most prominent
    • 60–70% of cases
    • sometimes vastly dominant
    • usually undifferentiated histologic profile
    • may fashion Homer Wright, Flexner–Wintersteiner or ependymoblastic-type rosettes
• Some contain ependymal canals or neural tube-like structures within primitive neuroepithelial compartment
• Spindle cell mesenchymal components:
  • in ≈30%
  • often fetal mesenchyme-like appearance
• Epithelial elements:
  • may be represented by:
    • cohesive cell nests
    • glands
    • adenoid structures
    • keratinizing squamous islands
  • in ≈25%
• Differentiation along striated muscle lines not reported

Special Stains and Immunohistochemistry

• Usually complex1,2
• Rhabdoid and nonrhabdoid large cell elements:
  • invariably label for vimentin:
    • intense labeling of cytoplasmic inclusions when present
  • nearly always immunoreactive for EMA:
    • may be diffuse or confined to cytoplasmic membranes
  • commonly label for:
    • GFAP
    • SMA
      • antibodies to SMA occasionally label peripheral cytoplasmic ring with particular intensity (a pattern encountered in some smooth muscle tumors)
• Large cell components:
  • commonly immunoreactive for cytokeratins (AE1/3; CAM 5.2)
  • sometimes immunoreactive for neurofilament protein (NFP) and synaptophysin (SYN)
  • desmin reactivity in only a minority:
    • usually restricted to mesenchymal or PNET-like regions:
      • may also label for:
        • NFP
        • SYN
        • GFAP
  • finely granular α-fetoprotein staining reported1
• Epithelial elements:
  • label for:
    • cytokeratins
    • less commonly, EMA
• Uniformly negative for:
  • placental alkaline phophatase (PLAP)
  • β-human chorionic gonadotropin (β-HCG)

Diagnosis

• Some ostensibly pure medulloblastomatous or PNET-like appearance:
  • may represent ‘lopsided’ variant:
    • occasionally display monosomy 22 or deletions/mutations involving INI 1:5,6
      • foreign to primitive neuroepithelial neoplasms
• Some tumors reported as medulloblastomas or pineoblastomas in association with renal RTs of infancy and early childhood7 may have been AT/RTs of exclusively neuroepithelial appearance complicating constitutional INI 1 mutations

Other Investigations

• MRI:
  • typically bulky mass
  • often partly cystic and hemorrhagic
  • profile indistinguishable from medulloblastoma/PNET
    • usually
      • T1 hypointensity
      • T2 iso/hypointensity
      • contrast enhancement

Differential Diagnosis

• Rhabdoid variants of choroid plexus carcinoma and germ cell tumors
• Neoplasms of disparate histogenesis that can assume rhabdoid guises and arise within or secondarily involve CNS:
  • principal considerations given location, age group and frequent presence of embryonal neuroepithelial elements are:
    • medulloblastoma, including ‘large cell’ variant
    • pineoblastoma
    • other primitive neuroepithelial tumors (central PNETs) arising within supratentorial and intraspinal compartments
• Embryonal neoplasms of central neuroepithelial derivation and other tumors that occasionally exhibit rhabdoid features:
  • AT/RTs can usually be differentiated by complex immunophenotype, particularly:
    • colabeling of large cell elements for:
      • vimentin
      • EMA
      • GFAP
      • SMA
  • assessment of chromosome 22/INI 1 status:
    • may be required in ambiguous cases8
    • unmasks AT/RTs presenting as medulloblastomas/PNETs of infancy

Genetics

• Gene expression studies confirm activation of a myogenic differentiation program10
• >90% characterized by monosomy/deletions or mutations involving chromosome 22q
• FISH may be applied to paraffin-embedded tissues for this purpose1,8
• Apparently responsible gene:
  • hSNF5/INI 1
  • maps to 22q11.2
  • codes for ubiquitously expressed protein that is member of SWI/SNF complex:3,4
    • apparently involved in conformational alterations in nucleosome that influence histone–DNA binding, thus facilitating transcription factor access
• INI 1 alterations also characterize subset of:
  • choroid plexus carcinomas
  • select tumors histologically indistinguishable from medulloblastomas and supratentorial PNETs3
    • familial occurrence of these tumor types in various combination constitutes syndrome associated with germline INI 1 mutation5,6

Prognosis

• ≈50% die within 6 months
• Survival >1 year exceptional