—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 5 - Sclerosing Perineurioma (PN) of the Foot, Subcutaneous,
with Giant Spiral Collagen Rosettes and Ribosome-lamella Complexes

Dominic V. Spagnolo
The Western Australia Centre for Pathology
Nedlands, Australia


Click on each slide thumbnail image for an enlarged view
Clinical History:
58 year-old female with a painless mass on the instep of the right foot, slowly growing for at least the past 5 years. The mass was subcutaneous and had no neurovascular, muscular or fascial attachments. There is no evidence of recurrence 2.5 years after excision.


Case 5 - Figure 1 - Scanning magnification showing a well-circumscribed, lobulated lesion composed of alternating cellular areas with hypocellular, myxohyaline areas.
Case 5 - Figure 2 - Higher magnification from hyaline area showing scant epithelioid cells set agains a densely collagenized stroma.
Case 5 - Figure 3 - Higher magnification from more cellular area showing proliferation of bland spindle cells adopting a whorling pattern and embedded in a myxoid stroma.

Pathologic Findings:
The specimen was a circumscribed, firm, ovoid nodule measuring 40 x 30 x 25 mm. Its cut surface was lobulated, with ill-defined and variably-sized nodules of firm white tissue, surrounded by somewhat myxoid pale yellow bands. Microscopic:The key findings are distinct lobularity, particularly peripherally, alternating moderately cellular and hypocellular myxohyaline areas, giant collagen rosettes and spindle and epithelioid cells. The cellular areas contain spindle cells with bland fusiform nuclei and long ill-defined cytoplasmic processes, arranged in lamellae and distinct whorls and associated with a myxoid or collagenous stroma. In the hyaline areas the cells have an epithelioid morphology and are arranged in clusters, trabeculae, cords and whorls. Mitoses are extremely rare. Cellularity increases around some of the collagen rosettes, and the cells here are often plumper. Immunohistochemistry: Both spindle and epithelioid cells are diffusely EMA+, vimentin+, and are surrounded by collagen IV (and weaker laminin) staining. Negative immunostains include: Keratins, S-100 protein, GFAP, CD57, alpha-smooth muscle actin, desmin, CD31, CD34, factor XIIIa. Ultrastructure:Both spindle and epithelioid cellsareorganelle-poor. Key findings are patchy external lamina, pinocytotic vesicles and sparse intermediate junctions. Occasional cells contain ribosome-lamella complexes. The giant collagen rosettes are composed of normally periodic spiral (frayed) collagen fibrils of either normal (20-100 nm) or coarse (up to 140 nm) width. There are no giant (>200 nm) fibrils (therefore NOT amianthoid).

Diagnosis - Sclerosing Perineurioma (PN) of the Foot, Subcutaneous, with Giant Spiral Collagen Rosettes and Ribosome-lamella Complexes

Discussion:
Sclerosing PN were first reported by Fetsch et al1. The index case differs in its location on the foot, the occurrence of ribosome-lamella complexes, and the formation of giant spiral collagen rosettes. While intraneural PN has been recognized for at least 20 years, albeit originally as localized hypertrophic neuropathy (LHN), only recently has there been increasing recognition of soft tissue PN as an entity. The term 'perineurioma' in the context of extraneural tumours was first coined by Lazarus and Trombetta in 1978 based on their ultrastructural studies2. 'Storiform neurofibroma' and 'storiform perineurial fibroma' of Harkin and Reed (AFIP second series fascicles) also most likely represent examples of PN. Defined as a soft tissue tumour of differentiated perineurial cells3, PN requires positive identification of perineurial cells either by immunohistochemistry (IHC) or electron microscopy (EM). The spectrum of perineuriomas includes:

  1. Intraneural perineurioma (IPN; with pseudo-onion bulb formation)
  2. Soft tissue perineurioma (STPN), including the variants (i) Sclerosing PN (having characteristic clinicopathologic features)1, and (ii) Reticular PN (a morphologic pattern only)4,5.
  3. Malignant perineurioma
    1. Intraneural perineurioma3,6 - There is good evidence that IPN is neoplastic in nature (significant cell proliferation index; clonal chromosome 22 abnormalities6,7). It is a rare, benign, localized, intraneural lesion, usually affecting large nerves of the upper or lower extremity in young people, which may cause weakness and muscle atrophy6. It causes fusiform enlargement of the nerve over a variable length. Most readily appreciated on cross-section are pseudo-onion bulbs of multilayered, EMA+/S-100- perineurial cells whorling around one or more central axons, their myelin sheaths and Schwann cells, collagen or small vessels. In longstanding cases, there may be considerable sclerosis.
    2. Extraneural soft tissue perineurioma - STPN is an uncommon tumour7, and not all cases reported as such fulfil minimum diagnostic requirements. STPN occurs more frequently in women (sclerosing PN excepted), most often middle-aged and there is no known NF1 or NF2 association. Most occur in the subcutis of limbs or trunk, uncommonly in deep soft tissues of the trunk and extremities, and seldom in other locations3, including skin8 where they can show features of both sclerosing and intraneural PN9. PN are circumscribed, rubbery, gray/white nodules generally <4 cms, rarely associated with a nerve. They are variably cellular and may include densely cellular areas8,10. The prototype cells have elongated, thin and wavy, bipolar, eosinophilic cell processes. Nuclei are delicate, often buckled or wavy and have tapered ends. Epithelioid cells may occur8,10. Mitoses are rare. The cells occur in bundles, lamellae, fascicles, whorls and storiform arrangements. The stroma is variably collagenous and myxoid. Small vessels are frequent and perivascular whorling of cells may occur. Necrosis, cystic degeneration, nucleomegaly, smudgy hyperchromasia, dystrophic calcification or ossification are very uncommon3. By IHC, diffuse membrane EMA staining and lack of S-100 protein are definitional. Recently, claudin-1, a novel tight junction-associated protein has been shown to be a sensitive adjunctive marker of perineurioma11. Pericellular basement membrane is highlighted by staining for collagen type IV and laminin (the latter weaker and focal). Focal positivity for keratin and smooth muscle actin occurs in a minority of cases, and variable CD34 positivity may occur in 30-40% of STPN 5. Ultrastructural characteristics of PN are long, thin cellular processes often enshrouding collagen bundles, few organelles, sparse filaments, discontinuous external lamina, sparse and rudimentary intercellular junctions and tight junctions and many micropinocytic vesicles2,10,12,13. The finding of ribosome-lamella complexes in several cells, as in this case, has been noted in one previous report14, and while of interest, has no diagnostic specificity. Partial or total deletion of chromosome 22 has been demonstrated in STPN by cytogenetics15 and FISH7, and more recently, inactivating point mutations in the NF2 gene have been found in 50% of cases16.
    3. Sclerosing PN. - Recently described1, these are acrally located in the subcutis (+/- dermis) of the digits and palms of mainly young males, measure <5.0 cms in diameter and form rubbery, circumscribed masses. They are composed of bland, small epithelioid, or plump spindled cells arranged in cords, clusters, trabeculae or onion bulb-like formations, often with perivascular whorling. The stroma is often densely collagenous and hyalinized. The ultrastructural and IHC profiles are typical of PN; a minority of cases are focally keratin+, and about half are muscle-specific and alpha-smooth muscle actin+. Recurrence is not recorded. Bilateral occurrence has since been reported17, and some have been predominantly intradermal9,18.
    4. Reticular or retiform PN - 4,5 is a morphologic variant of PN. It has a distinctive lace-like growth, with anastomosing fusiform or spindly cells disposed in a myxoid or myxohyaline stroma, creating a meshwork of psudocystic or cystic spaces containing myxoid stroma or collagen. Occasional cases may be extensively hyalinized.
  4. Malignant PN (MPN) - A small proportion, probably <5%19, of malignant peripheral nerve sheath tumours (MPNST) have been shown to demonstrate perineurial cell differentiation based on EM and/or IHC features13,19-22. Ultrastructural perineurial characteristics vary depending on the grade of the tumour, and some cases may exhibit hybrid perineurial and Schwann cell features19. MPN are unencapsulated growths with infiltrative margins, they rarely show an association with a nerve, and demonstrate variable nuclear pleomorphism, mitotic activity and necrosis. The limited follow-up data available suggest that MPN may have a better prognosis than conventional MPNST19.

    Giant collagen rosettes composed of normally periodic, spiralled or "frayed" collagen were prominent in the case presented. Fibril widths varied but were not amianthoid. Collagen rosettes or "collagen crystalloids" is a histologic descriptor without ultrastructural specificity, and may be composed ultrastructurally of normal, amianthoid, or spiralled collagen. Rosettes have been described in an array of neoplastic and non-neoplastic conditions (reviewed by Eyden23), and in some reports are inappropriately referred to as "amianthoid" collagen . "Amianthoid" should only be used when ultrastructurally proven giant collagen fibrils (>200 – 1000+ nm wide) constitute part or all of the rosette. Spiralled, or helical collagen fibrils have a normally banded, spiralled appearance in longitudinal sections, and their edges appear ragged or frayed in cross-sections. Spiralled collagen has been described in various non-neoplastic conditions, is possibly under-reported in neoplasms, and it has not been described before in PN.


Differential Diagnosis:
A number of benign, borderline or low-grade malignant spindle and/or epithelioid cell lesions enter the differential diagnosis of PN. Most are readily excluded by a consideration of location, morphology, IHC staining and EM.

The benign conditions that may mimick STPN include fibroma of tendon sheath; Schwannoma and neurofibroma; neurothekeoma; circumscribed storiform collagenoma; tenosynovial giant cell tumour; fibromatosis; desmoplastic fibroblastoma and solitary fibrous tumour. Localized hypertrohic neuropathy ,LHN  while morphologically similar to IPN, can be distinguished by IHC and EM. LHN forms true "onion bulbs" (concentric arrays of Schwann cells separated by collagen, disposed around a central unmyelinated axon) while IPN forms "pseudo-onion bulbs" and has chromosome 22 anomalies (see above).

Potentially more aggressive in behaviour are the following differential diagnostic entities.

Soft tissue myoepithelioma and sclerosing adnexal tumours can resemble conventional and sclerosing PN, depending on their composition. They may contain spindle, epithelioid, clear and plasmacytoid cells, adnexal tumours may show gland formation, the stroma can be myxo-hyaline, and collagen rosettes may occur. They are S-100+, keratin+, alpha-smooth muscle actin+ in 50% of the cases, and variably express GFAP, EMA, desmin and calponin.

Ossifying fibromyxoid tumour (OFMT) may resemble both reticular and sclerosing PN. It also presents in subcutaneous tissues of the extremities and trunk and is characteristically lobulated. OFMT often has a partial peripheral shell of bone, its cells are more rounded and uniform in appearance and have eosinophilic cytoplasm. Most are diffusely S-100+, desmin is often positive and EMA would be expected to be negative.

Epithelioid hemangioendothelioma (EHE) shares similarities with sclerosing PN. It has myxohyaline stroma and epithelioid cells (which may form neolumina) arranged in cords, clusters and trabeculae. EHE is often associated with a vessel, usually a vein. It is CD31+, Factor VIIIR-Ag+, CD34+, EMA-. By EM, pinocytic vesicles may be a source of diagnostic confusion, but EHE has a much better developed basal lamina, tight junctions between cells, the cells are intermediate filament-rich and Weibel-Palade bodies may be present.

Low grade myofibroblastic sarcoma (LGMFS) are usually deeply located and have infiltrative margins. They are moderately cellular, but may be sclerotic. The cells are plump, have fusiform, moderately pleomorphic and hyperchromatic nuclei, and there is mitotic activity. The cells are myofibroblastic (EMA-, SMA+/-, desmin+, laminin- and collagen IV-).

Low grade fibromyxoid sarcoma (LGFS) andhyalinizing spindle cell tumour with giant rosettes (HSCTGR) are now considered morphological variants of a single entity. LGFS has a swirling pattern of alternating myxoid foci and hypocellular fibrous zones. These are bland fibroblastic lesions (although foci of hypercellularity and atypia may occur) which are EMA-.

Extraskeletal myxoid chondrosarcoma (EMC) can resemble reticular PN, but EMC is deeply seated, often intramuscular, and its cells are typically larger and have eosinophilic cytoplasm. IHC may not be helpful as EMC may be S-100+ and EMA+, but a proportion of EMC express neuroendocrine markers, and they are ultrastructurally and cytogenetically distinct.

References

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