Perineuroma, storiform perineural fibroma

Definition

Perineuromas are uncommon benign tumours of peripheral nerve sheaths with morphological, ultrastructural and immunohistochemical features that distinguish them from Schwannomas and neurofibromas. The diagnosis depends on morphology combined with either EMA-positive / S-100-negative immunohistochemistry or ultrastructural evidence.

Epidemiology

Perineuromas over a wide age range. They have variously been reported to show a female predominance5 or to occur with equal frequency in men and women. Intestinal cases may be more common in women3. There is no association with neurofibromatosis.

Clinical presentation

The tumours occur over a wide range of anatomical sites, including lower9,17 and upper limbs10 and limb girdles12, trunk11,14,15, head16 and neck15, retroperitoneum. They may occur in the subcutis7,15 or deep soft tissues7,15, less often in the dermis5,7. Rare sites include breast13, intestines3, the uterine cervix, testis and paratesticular tissue.

Intestinal cases often present as asymptomatic small sessile mucosal polyps at colonoscopy, sometimes with obstructing mass lesions3. Most cases occur in the large bowel, but one case has been reported from the small bowel3.

Gross appearance

The tumours are almost always grossly well circumscribed but are not encapsulated. They may appear lobulated7. Most are firm or rubbery, some soft. There may be focal haemorrhage, central necrosis or infarction. Dermal cases, tend to be dumbbell-shaped, extending into the subcutis5.

Histopathology

The tumours are unencapsulated. Most are well circumscribed but some show focally infiltrating margins7. Cellularity varies7. They are characterised by a whorled (storiform) growth pattern. In some cases, the whorls are perivascular. Occasionally there may be marked nuclear palisading. The spindle cells are very thin with serpentine nuclei. Some cases also contain more ovoid, polygonal or epithelioid cells5,7. The mitotic rate is very low. The stroma is usually collagenous but often shows a myxoid component14. Isolated cases have shown calcospherites15, osseous metaplasia17 and xanthoma-like cells7. There may be a mild chronic inflammatory cell infiltrate7.

Intestinal cases are usually intramucosal, replacing the lamina propria, with entrapment of crypts. The entrapped epithelium may be hyperplastic, resembling a hyperplastic polyp. The spindle cells of the tumour may form whorls around crypts. Larger tumours may infiltrate through the bowel wall3.

The presence of epithelioid cells has been described only in dermal cases5.

Variant

• Intraneural perineuroma (localised hypertrophic neuropathy) shows concentric intraneural lamellar proliferation of perineural cells resulting in a sausage-shaped swelling of a segment of nerve. There are EMA-positive cells surrounding a central core of axons, positive for S-100 and neurofilament. This variant may be a reactive process in response to nerve damage15, since it commonly occurs in the interosseous nerve of young adults. However, intraneural perineuroma, soft tissue perineuroma and localised hypertrophic neuropathy may all show deletions of chromosome 2216.

• Sclerosing perineuroma occurs exclusively in the hand of young adults, predominantly males, and consists of cords of bland epithelioid cells within a densely sclerotic stroma. There may be an onion-skin growth pattern sometimes swirling around blood vessels or small nerves18. A PAS stain shows basement lamina-like material around the epithelioid cells18. One cutaneous case has also been reported to be sclerosing5. One case has been reported which incorporated axons centrally and showed a deletion of chromosome 228.

• Soft tissue perineuroma

• Reticular perineuroma

Immunohistochemistry parallels that of the normal perineural cell:

Ultrastructure

Long bipolar processes, numerous pinocytotic vesicles and tight junctions are present. There are discontinuous external laminae7,9,12,17,18. (By contrast, Schwannomas show interdigitating cytoplasmic processes and continuous external laminae.)

Cytogenetics

Monosomy 22, eliminating one of the NF-2 alleles, has been reported in Schwannomas, neurofibromas and perineuromas20.

Differential diagnosis

Superficial tumours:

• fibrous histiocytoma, including the myxoid variant, epithelioid fibrous histiocytoma if there are epithelioid cells5.

• dermatofibrosarcoma protuberans: is also positive for CD34 and Factor XIIIa but is negative for EMA. DFSP is much more infiltrative.

• neurothekeoma: the spindle cells form lobules. There is positivity for S-100 with negativity for EMA.

• Cutaneous meningioma: the resemblance is increased in cases with epithelioid cells7 but cutaneous meningiomas are often ill-demarcated. Meningiomas, like perineuromas, are positive for EMA and vimentin. They differ in also being positive for cytokeratins, S-100 and desmoplakin.

Deep tumours:

• Schwannoma

• Neurofibroma: including the perineurial-rich variant which is positive for EMA.

• Solitary fibrous tumour: the architecture is patternless. There are pericytoma-like branching blood vessels. Also positive for CD34 and may be positive for EMA.

• perineural MPNST: show hypercellular perivascular accentuation. There is marked cytological atypia and there are frequent mitoses.

• low-grade fibromyxoid sarcoma: the collagenous and myxoid stroma forms alternating zones. There are arcades of small blood vessels. There may be giant collagen "rosettes". May be positive for EMA. Demonstration of t(7;16) is diagnostic.

• cellular myxoma; lack even focal storiform areas. EMA is negative.

• low-grade myxofibrosarcoma: there are vacuolated "pseudolipoblasts", perivascular hyperchromatic cells and long curvilinear blood vessels.

Intestinal:

intramucosal;

• • ganglioneuroma, ganglioneuromatous polyposis, diffuse ganglioneuromatosis. Ganglioneuromas also have ill-defined margins and entrapped crypts. There is a combination of S-100 positive Schwann cells and ganglion cells and neurofilament positive axons.

  • neurofibroma: rare in the gastrointestinal tract. Positive for S-100.

  • leiomyoma: sharply circumscribed without entrapped crypts, the spindle cells have eosinophilic cytoplasm. Positive for SMA and desmin.

  • benign fibroblastic polyp: similar cytomorphology and entrapped crypts. Also associated with hyperplastic polyps. But negative for EMA.

submucosal;

• • GIST: positive for CD117 and often positive for caldesmon.

  • Schwannoma: at this site are also unencapsulated, often surrounded by a lymphoplasmacytic infiltrate. Positive for S-100 and GFAP but negative for EMA.

Sclerosing perineuroma of the hand:

• fibroma of tendon sheath

• sclerotic fibroma of skin associated with Cowden's syndrome

• late stage tenosynovial giant cell tumour

• sclerosing adnexal tumour: positive for cytokeratins as well as for EMA.

• epithelioid haemangioendothelioma: positive for CD31, CD34 and Factor VIIIRA.

• epithelioid neurofibroma

• regressing glomus tumour: strongly positive for HHF35 and SMA but negative for EMA.

• calcifying fibrous pseudotumour (childhood fibrous tumor with psammoma bodies): negative for EMA18.

It has been suggested that Claudin-1 may be useful in the differentiation from other tumours, although the rates of positivity of perineuromas for Claudin-1 have been variable in two studies1,2.

Prognosis

These tumours are benign5,18. Local recurrence may rarely occur. Scattered pleomorphic cells or infiltrating margins have no sinister significance.

There are occasional malignant peripheral nerve sheath tumours with perineural differentiation ("malignant perineuroma")4,19. The behaviour of atypical cellular perineuromas requires further long-term study6.

References

1 Folpe, A.L., Billings, S.D., McKenney, J.K., Walsh, S.V., Nusrat, A. and Weiss, S.W. Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol 2002;26:1620-6.

2 Hornick JL, Fletcher CD. Soft tissue perineurioma: clinicopathologic analysis of 81 cases including those with atypical histologic features. Am J Surg Pathol 2005; 29:845-58

3 Hornick JL, Fletcher CD. Intestinal perineuriomas: clinicopathologic definition of a new anatomic subset in a series of 10 cases. Am J Surg Pathol 2005; 29:859-65

4 Zamecnik M, Michal M. Malignant peripheral nerve sheath tumor with perineurial cell differentiation (malignant perineurioma). Pathol Int 1999; 49:69-73

5 Robson AM, Calonje E. Cutaneous perineurioma: a poorly recognized tumour often misdiagnosed as epithelioid histiocytoma. Histopathology 2000; 37:332-9

6 Zamecnik M, Koys F, Gomolcak P. Atypical cellular perineurioma. Histopathology 2002; 40:296-9

7 Mentzel T, Dei Tos AP, Fletcher CD. Perineurioma (storiform perineurial fibroma): clinico-pathological analysis of four cases. Histopathology 1994; 25:261-7

8 Sciot R, Cin PD, Hagemeijer A, et al. Cutaneous sclerosing perineurioma with cryptic NF2 gene deletion. Am J Surg Pathol 1999; 23:849-53

9 Lazarus SS, Trombetta LD. Ultrastructural identification of a benign perineurial cell tumor. Cancer 1978; 41:1823-9

10 Inaba H, Hizawa K, Ii K, et al. Perineurioma. A distinctive form of the peripheral nerve tumor. Tokushima J Exp Med 1980; 27:37-43

11 Ushigome S, Takakuwa T, Hyuga M, et al. Perineurial cell tumor and the significance of the perineurial cells in neurofibroma. Acta Pathol Jpn 1986; 36:973-87

12 Weidenheim KM, Campbell WG, Jr. Perineural cell tumor. Immunocytochemical and ultrastructural characterization. Relationship to other peripheral nerve tumors with a review of the literature. Virchows Arch A Pathol Anat Histopathol 1986; 408:375-83

13 Carneiro F, Brandao O, Correia AC, et al. Spindle cell tumor of the breast. Ultrastruct Pathol 1989; 13:593-8

14 Lopez JI, Elizalde JM. A case of perineurioma with prominent myxoid changes. Arch Anat Cytol Pathol 1992; 40:220-2

15 Tsang WY, Chan JK, Chow LT, et al. Perineurioma: an uncommon soft tissue neoplasm distinct from localized hypertrophic neuropathy and neurofibroma. Am J Surg Pathol 1992; 16:756-63

16 Giannini C, Scheithauer BW, Jenkins RB, et al. Soft-tissue perineurioma. Evidence for an abnormality of chromosome 22, criteria for diagnosis, and review of the literature. Am J Surg Pathol 1997; 21:164-73

17 Rank JP, Rostad SW. Perineurioma with ossification: a case report with immunohistochemical and ultrastructural studies. Arch Pathol Lab Med 1998; 122:366-70

18 Fetsch JF, Miettinen M. Sclerosing perineurioma: a clinicopathologic study of 19 cases of a distinctive soft tissue lesion with a predilection for the fingers and palms of young adults. Am J Surg Pathol 1997; 21:1433-42

19 Hirose T, Sumitomo M, Kudo E, et al. Malignant peripheral nerve sheath tumor (MPNST) showing perineurial cell differentiation. Am J Surg Pathol 1989; 13:613-20

20 Hahn HP, Fletcher CDM. The role of cytogenetics and molecular genetics in soft tissue tumour diagnosis - a realistic approach. Current Diagnsotic Pathology 2005;11:361-370.

This page last revised 30.8.2005.

©SMUHT/PW Bishop