Stanford School of Medicine

Surgical Pathology Criteria

 use browser back button to return



  • A tumour composed entirely of neoplastic perineurial cells. Tumors may be intraneural or within the soft tissue
  • See separate description of Gastrointestinal Tract Perineurioma

Alternate/Historical Names

  • Localized hypertrophic neuropathy

Diagnostic Features

  • Spindle cell proliferation
    • Characteristic long, thin, delicate, bipolar cytoplasmic processes
    • Pale, eosinophilic cytoplasm
  • Wavy or tapering nuclei
    • finely distributed chromatin
  • By definition, immunohistochemical staining positive for EMA and S100 negative
    • Immunophenotype matches normal perineurial cells
    • EMA staining varies from focal, weak to strong, diffuse
      • Highlights delicate bipolar cytoplasmic processes
      • May require procedure variation to increase sensitivity for EMA
      • Examples of ultrastructurally diagnosed EMA-negative perineuriomas exist
    • Often express Claudin-1, and GLUT.
      • May express CD34 and actins
  • Perivascular whorls
  • Mitotic activity may be present
    • 0-13/30 high-power (40x with 10x oculars) fields (mean of 1)
    • 65% of tumors having none
  • May have degenerative atypia
    • Changes include nuclear pleomorphism, hyperchromasia, cytoplasmic-nuclear inclusions
    • Most common in long-standing tumors
  • As a rule, necrosis is absent


  • Intraneural Perineurioma
    • Neoplastic perineurial cells proliferating throughout the endoneurium
      • Form repetitive concentric layers around nerve fibers forming characteristic pseudo-onion bulbs
        • Pseudo-onion bulbs best appreciated on cross-section
        • Due to organized architecture, may be mistaken for reparative or reactive process
      • Produce segmental, tubular enlargement of the affected nerve
      • Residual S100-positive nerve fibers are surrounded by EMA-positive perineurial cells
    • WHO grade I
      • Do not undergo malignant transformation
    • Frequently present with muscle weakness with or without obvious atrophy
      • sensory disturbances are rare
    • Most common in peripheral nerves of extremities in young adults
      • Most common in upper extremity
  • Extraneural (Soft Tissue) Perineurioma
    • ┬áNot grossly associated with a nerve
    • Solitary, generally small (usually <10 cm)
    • Well-circumscribed, but not encapsulated
    • Varying growth patterns
      • Storiform most common
      • Can also show lamellar, whorled, pacinian, or fascicular patterns
    • Often collagenous stoma
      • Up to 20% contain at least focal myxoid stroma
    • Present with non-specific mass effect
    • More common in superficial soft tissue of trunk and extremities particularly the hands
  • Sclerosing Perineurioma
    • Extraneural (soft tissue) perineurioma variant
    • Plump spindled and epithelioid tumor cells in a hyalinized stroma
    • Prominent thin-walled vessels
      • Perivascular and lace-like arrangement tumor cells around vessels
    • Described occurring mainly in the fingers of young males
  • Reticular Perineurioma
    • Extraneural (soft tissue) perineurioma variant
    • Prominent degenerative myxoid changes
      • May form pseudocystic spaces
    • Tumor cells show lace-like, reticular pattern
  • Malignant Perineurioma (Perineurial MPNST)
    • Features of malignant perineuriomas
      • Hypercellularity
      • Nuclear atypia
      • Hyperchromasia
      • High mitotic rate
      • Infiltrative growth
      • Necrosis
        • The presence of necrosis upgrades from WHO grade 2 to 3
    • Arise exclusively from Extraneural (soft tissue) perineuriomas
    • Very uncommon
    • Less likely to metastasize than conventional MPNSTs
  • Gastrointestinal Perineurioma


  • Benign, rarely recur
    • Surgical resection with negative margins is usually curative
  • Sporadic tumors
    • Rare cases reported in patients with NF1 or NF2

Differential Diagnosis

  • Intraneural Neurofibroma/Schwannoma
  • Neurofibroma
  • Intraneural MPNST
  • Neural lipofibroma
  • Pacinian Neuroma
  • Low-grade fibromyxoid sarcoma
  • Ectopic Meningioma
  • Desmoid fibromatosis
  • Smooth Muscle tumor
  • Solitary fibrous tumor
  • Superficial acral myxoma
  • Dermatofibroma
  • Dermatofibrosarcoma protuberans

Intraneural Perineurioma

Intraneural Neurofibroma/Schwannoma

S100 negative

Express S100

Pseudo-onion bulb formation


Closely encircle nerve fibers

Nerve fibers scattered (neurofibroma) or at periphery (schwannoma)


Extraneural Perineurioma


S100 negative

Express S100

May have collagenous stroma

“Shredded Carrot” collagen bundles

Both may express CD34 and EMA as neurofibromas have a perineurial component

Intraneural Perineurioma

Intraneural MPNST

Uniform cylindrical shape

Fusiform or eccentric mass

Pseudo-onion bulb formation


Expresses EMA

EMA Negative (except in areas of glandular differentiation)

S100 Negative

May express focal or weak S100

Mitoses may be present in both lesions

Intraneural Perineurioma

Nveural Fibrolipoma

Purely perineural proliferation

Mature adipose tissue and fibrous tissue proliferation

Both may show pseudo-onion bulb formation and express EMA and CD34

Intraneural Perineurioma

Pacinian Neuroma

Neoplastic, not associated with trauma

Hyperplastic/hypertrophic, frequently associated with prior trauma


Often painful

Segmental enlargement of nerve

Enlarged or multiple pacinian corpuscles

Varied locations, may occur on hands

Most commonly on hands, especially fingers

Both may contain concentric onion-like proliferations. In both, perineural cells stain with EMA and residual nerve fibers stain with S100

Extraneural Perineurioma

Low-grade Fibromyxoid Sarcoma

Monosomy chromosome 22

Characteristic FUS-CREB3L2 translocation (chromosomes 7 and 16)

MUC 4 Negative

Express MUC4


Grossly-circumscribed, but microscopically infiltrative

Alternating pattern not prominent

Alternating fibrous and myxoid areas

Myxoid areas infrequent

Myxoid areas definitional

Express EMA (definitional)

Occasional, focal, weak EMA

Collagen rosettes absent

Occasional giant collagen rosettes

Both may express Claudin-1

Extraneural Perineurioma

Ectopic Meningioma


Infiltrative growth

Long, thin, spindled cells

Syncytial epithelioid cells

Varied architecture, may form whorls

Whorled architecture

Psammoma bodies absent

Frequent Psammoma bodies

Intranuclear inclusions absent

Frequent intranuclear pseudoinclusions

Both express EMA and Claudin-1

Extraneural Perineurioma

Desmoid Fibromatosis


Ill-defined, invasive growth

Variable architecture

Broad, sweeping fascicles

Nuclear Beta-catenin absent

Nuclear Beta-catenin staining often

Infrequently express actins

Express smooth muscle actin and muscle-specific actin


Extraneural Perineurioma

Smooth Muscle Tumors

Wavy or tapering nuclei

Blunt-ended nuclei

Characteristic long, thin, delicate, bipolar cytoplasmic processes

Abundant eosinophilic cytoplasm

Negative for actins and desmin

Express actins and desmin

Variable architecture

Perpendicular intersecting fascicles


Extraneural Perineurioma

Solitary Fibrous Tuvmor

Staghorn vessels absent

Prominent vascular pattern with staghorn vessels

Variable patterns

“Patternless” pattern (alternating and varying cellularity and pattern)

Express EMA

Variable EMA expression

No characteristic gene fusion

NAB2-STAT6 gene fusion

STAT6 negative

Express STAT6

May express CD34

Diffuse CD34 expression


Extraneural Perineurioma

Superficial Acral Fibromyxoma

Usually on extremities or trunk, infrequently periungual

Most common on hands or feet and often periungual

Express EMA

May express EMA (~50%)

May express CD34

Express CD34

Express Claudin-1

Claudin-1 Negative


Extraneural Perineurioma


No epidermal induction

Hyperplastic epidermis

Long, thin, spindled cells

Plump, spindled and histiocytoid cells

EMA positive

EMA may be focal or weak


Infiltrative growth


Extraneural Perineurioma


May express CD34

Strong, diffuse CD34 expression

Express EMA

EMA focal or weak

May have storiform architecture

Characteristic storiform architecture

Usually centered in subcutaneous tissue and well-circumscribed

Centered in dermis often invading subcutaneous tissue

No characteristic gene fusion

Characteristic COL1A-PDGFB fusion



  • Goldblum, J.R., Folpe, A. L., Weiss, S.W., Enzinger and Weiss's Soft Tissue Tumors. 6th ed 2014. Philadelphia, PA: Mosby Elsevier.
  • Scheithauer B.W., Woodruff J.M., Erlandson R.A. Tumors of the Peripheral Nervous System, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 24, 1999.
  • Macarenco R.S., Ellinger F., Oliveira A.M. Perineurioma: a distinctive and underrecognized peripheral nerve sheath neoplasm. Arch Pathol Lab Med. 2007 Apr;131(4):625-36.
  • Fisher, C. et al. Diagnostic pathology: Soft tissue tumors. Amsirsys, 2011.
  • Fletcher, C.D.M. et al. WHO Classification of Tumours of Soft Tissue and Bone. IARC, Lyon, 2013.
  • Louis, D.N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K. eds. WHO Classification of Tumours of the Central Nervous System, Fourth Edition. IARC Press: Lyon 2004

Kurt Schaberg MD
Donald Born MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting :1/15/16

Printed from Surgical Pathology Criteria:
© 2005  Stanford University School of Medicine