V-5A. Intraneural perineurioma/localized hypertrophic

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TUMORAL, QUASITUMORAL AND PSEUDOTUMORAL LESIONS OF SOFT TISSUE
9
References
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2
3
4
5
6
7
8
Theaker JM, Gatter KC, and Puddle J. Epithelial membrane antigen expression by the perineurium of peripheral nerve and in peripheral nerve tumors. Histopathology 1988;13:171-9.
Theaker JM, Fletcher CDM. Epithelial membrane antigen expression by the perineurial cell: further studies of peripheral nerve lesions. Histopathology 1989;14:581-92.
Perentes E, Nakagawa Y, Ross GW, Stanton C, Rubinstein LJ. Expression of epithelial membrane antigen in perineurial cells and
their derivatives. An immunohistochemical study with multiple
markers. Acta Neuropathol (Berl.) 1987;75:160-5.
Ariza A, Bilbao JM, Rosai J. Immunohistochemical detection of
epithelial membrane antigen in normal perineurial cells and perineurioma. Am J Surg Pathol 1988;12:678-83.
Erlandson RA. The enigmatic perineurial cell cell and its participation in tumors and in tumor-like entities. Ultrastruct Pathol
1991;15:335-51.
Lazarus SS, Trombetta LD. Ultrastructural identification of a benign perineurial cell tumor. Cancer 1978;41:1823-9.
Mitsumoto H, Wilbourn AJ, Goren H. Perineurioma as the cause
of localized hypertrophic neuropath. Muscle Nerve 1980;3:403-12.
Bilbao JM, Khoury NJS, Hudson AR, Briggs SJ. Perineurioma
(localized hypertrophic neuropathy). Arch Pathol Lab Med
1984;108:557-60.
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Tsang WYW, Chan JKC, Chow LTC, Tse CCH. Perineurioma: an
uncommon soft tissue neoplasm distinct from localized hypertrophic neuropathy and neurofibroma. Am J Surg Pathol
1992;16:756-63.
Mitsumoto H, Estes ML, Wilbourn AJ, Culver JE. Perineurial
cell hypertrophic mononeuropathy manifesting as carpal tunnel
syndrome. Muscel Nerve 1992;15:1364-8.
Emory TS, Scheithauer BW, Hirose T, Wood M, Onofrio BM,
Jenkins RB. Intraneurial perineurioma. A clonal neoplasm associated with abormalitied of chromosome 22. Am J Clin Pathol
1995;103:696-704.
Tsang WYW. Perineuriomas: perineurial cell neoplasms with distinctive extra- and intra-neural forms. Adv Anat Pathol
1996;3:212-22.
Giannini C, Scheithauer BW, Jenkins RB, Erlandson RA, Perry
A, Borell TJ, 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.
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V-5A. Intraneural perineurioma/localized hypertrophic neuropathy
Intraneural perineurioma (IPN) is still referred to as localized hypertrophic neuropathy (LHN) (see above).
Older, inexact terms, such as intraneural neurofibroma,
hypertrophic neurofibrosis, and hypertrophic interstitial neuritis, have virtually been abandoned. IPN/LHN
is rare and, according to some authors 1-3, the case described in 1964 by Da Gama Imaginário et al. 4 is credited as the first example on record.
We have collected 73 cases from the literature 1-39, based on previous reviews for the period from 1965 up to
1996 2 3 28 32 40 and on electronic bibliography search
(pubmed) for the period from 1993 to the end of 2004.
We included all cases which were published as such,
but some would be excluded because of insufficient
data. But we did not include some other cases 40-46 which proved to be exemplary cases of localized “true
onion-bulb neuropathies” and which must be kept separate from true IPN/LHN (see below at differential
diagnosis).
Although several pathogenetic stimuli have been invoked in the past (e.g., trauma, microtrauma, ischaemia, inflammation, genetics, …), a neoplastic origin is
now virtually unanimously accepted.
CLINICAL FINDINGS
Males and females are equally affected. IPN/LHN mostly involves equally isolated major peripheral nerves of
the upper and lower extremities 2 24. Cranial nerves are
rarely involved 3. Uncommonly, there has been bilateral
symmetrical involvement 37, including an instance of two
simultaneously involved ipsilateral nerve roots (case 7
of Emory et al. 2). In the series of 8 cases contributed by
Emory et al. in 1995 2 and from the critical review analysis they performed on the 26 likely cases since published, the patients’ages ranged from 9 to 42 years. Young
adults are more often affected, but the disease has also
been observed in infancy 30 36 and in elderly 13.
In the series of Emory et al. 2, in descending order of
frequency the affected peripheral nerves are the posterior interosseus, median, sciatic, tibial, brachial plexus,
ulnar, radial, peroneal, femoral, and digital. Motor
symptoms are constant, sometimes accompanied by
sensory disturbancies: weakness, neurogenic muscle
atrophy, nerve palsy, sensory loss, Tinel’s sign, and focal tenderness may be present. Symptoms related to peculiar anatomical locations, e.g., carpal tunnel syndrome 21 30 are recorded. In one case a small unnamed nerve involvement has been documented 33 and in another
cases an intraosseous location (e.g. lower jaw bone 35)
has been observed. A localized mass is commonly
found. The duration of symptoms has ranged from a
few months to several years (up to 30 years 13) with a
mean of 76 months in the series of 15 patients reported
by Gruen et al. in their 15-year experience 24. Family
history or association with neurofibromatosis/NF-1 have not been reported. Clinically and intraoperatively a
fusiform peripheral nerve enlargement forming a localized rope-like mass is a constant finding (Fig. V-5Ai).
The size of the lesions has ranged from approximately
1 to 30 cm (mean, around 5-6 cm).
M. BISCEGLIA, ET AL.
100
PATHOLOGICAL FEATURES
The surgical specimen of IPN/LHN usually is represented by a small fascicular biopsy. Histologically, IPN
is composed of concentric layers of spindle cells forming pseudo-onion bulbs (Fig.V-5Aii), often surrounding myelinated or unmyelinated axons. Increase of the
interstitial collagen may be seen. In a unique case, a
partially reticular pattern – similar to the one described
in EPN – has been noted in association with the usual
pseudo-onion-bulb pattern, typical of IPN 35.
IMMUNOHISTOCHEMISTRY, ELECTRON MICROSCOPY,
AND SPECIAL STUDIES
The proliferating cells are immunoreactive for EMA
(Fig. V-5Aii: inset) and vimentin and are negative for
S-100 protein, CD34, desmin, and actins.
Ultrastructurally, the specific fine features of the perineurial cells, such as slender cytoplasmic processes
with discontinuous basal lamina, occasional tight junctions joining terminal cell processes, and numerous peripheral pinocytotic vesicles are usually visible and allow a confident diagnosis (Figs. V-5iii, V-5iv).
Cytogenetic studies and FISH analysis may demonstrate diverse abnormalities of chromosome 22 most commonly, or chromosome 14 2 35. Chromosome 22 is also
involved in several other tumors of neuroectodermal
origin (e.g., schwannoma, neurofibroma, meningioma,
glioma), including soft tissue perineurioma (see the appropriate section).
DIFFERENTIAL DIAGNOSIS
The differential diagnosis is twofold, clinically and
pathologically. Pathologically IPN/LHN is to be differentiated mainly from diffuse hypertrophic neuropathies. Diffuse hypertrophic neuropathies are characterized by the intraneural formation of onion bulbs, i.e.
laminated or concentric structures composed of EMA
negative and S-100 protein positive proliferating
Schwann cells, encircling axons, and causing multiple
enlargement of peripheral nerves. The prototypical
forms of diffuse hypertrophic neuropathies are represented by the hereditary and diffuse motor-sensory
polyneuropathy (HSMN) type I or Charcot-MarieTooth disease, hypertrophic form, and HSMN type III
or Dejerine-Sottas disease 47. However the family history, the clinical and molecular findings as well as the
histologic, immunophenotypical and ultrastructural
features enable the correct diagnosis. In our view,
onion bulbs made of proliferating Schwann cells and
their processes may well be called “true onion bulb
neuropathies”. True onion-bulb formations are also
seen in other systemic, genetic, metabolic or degenera-
References
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Suarez GA, Giannini C, Smith BE, Windebank AJ, Litchy WJ,
Dyck PJ. Localized hypertrophic neuropathy. Mayo Clin Proc
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tive conditions, such as Refsum disease, Krabbe’s disease, Roussy-Levi disease, metachromatic leukodystrophy, neurofibromatosis type 1, and diabetic neuropathy as well as in acquired diseases such as chronic inflammatory (demyelinating) poly(radiculo)neuropathy.
Finally true onion-bulb formation may also be seen in
some other rare localized diseases, such as “(localized)
hypertrophic inflammatory neuropathy” 48, which additionally is characterized by the presence of intraneural
mononuclear inflammatory cell infiltrates, and “localized true onion-bulb neuropathy”. “Localized true
onion-bulb neuropathy” is a non-inflammatory hypertrophic neuropathy, equalling histologically the classic
diffuse hypertrophic neuropathy but affecting single
nerves either spinal nerves 40 41 or cranial nerves 40-46,
which still waits a definite categorization. Localized
true onion-bulb neuropathy might even represent a fruste or incomplete expression of diffuse hypertrophic
neuropathy, which may later on manifest in its complete expression. Unfortunately “localized true onion-bulb
neuropathy” is currently known under the term of localized hypertrophic neuropathy 40 41 44-46, which – although semantically correct – is unfortunately misleading
in practice since, as previously stated, this same term is
also synonymic with IPN.
IPN/LHN may also enter the differential diagnosis of
EPN 38, but EPN is a tumor mass not associated with peripheral nerves, and its various histologic varieties (see
the appropriate section) are distinct from IPN/LHN.
Further, axons are present in IPN/LHN but not in EPN.
Another entity, of very recent description, which might
be considered in differential versus IPN/LHN, is represented by intraneural dendritic cell neurofibroma with
pseudorosettes 49: the only case so far reported of intraneural dendritic cell neurofibroma with pseudorosettes
exhibited a plexiform intraneural growth pattern involving several nerve twigs and is S-100 protein positive.
Further, pseudorosettes which typify this latter entity
can be easily distinguished from pseudo-onion bulbs of
INP/LHN even on morphological grounds.
Clinically IPN/LHN may be confused with several
other mass-forming neural lesions including fibrolipomatous hamartoma, lipoma, angioma, and neuropathic
amyloidosis, all of which are easily distinguished histologically.
BIOLOGICAL BEHAVIOUR
IPN/LHN is benign and malignant transformation has
not been observed. Preservation of neural integrity
should be the goal of treatment. For advanced cases, resection with autologous interposition graft repair has
been proposed 24.
2
3
Emory TS, Scheithauer BW, Hirose T, Wood M, Onofrio BM,
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Simpson DA, Fowler M. Two cases of localized hypertrophic
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Grossiord A, Lapresle J, Lacert P. A propos d’une forme localisée
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Lallemand RC, Weller RO. Intraneural neurofibromas involving
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Bilbao JM, Khoury NJS, Hudson AR, Briggs SJ. Perineurioma
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Ohnishi A, Kuroiwa Y, Kido M, Nakai R, Kuramitsu M. A case of
perineurioma showing radial nerve palsy – special reference to
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Tranmer BI, Bilbao JM, Hudson AR. Perineurioma: a benign peripheral nerve tumor. Neurosurgery 1986;19:134-8.
Iyer CV, Garretson HD, Byrd RP, Reiss SJ. Localized hypertrophic mononeuropathy involving the tibial nerve. Neurosurgery
1988;23:218-21.
Stanton C, Perentes E, Phillips L, VandenBerg SN. The immunohistochemical demonstration of early perineurial change in the
development of localized hypertrophic neuropathy. Hum Pathol
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Johnson PC, Kline DG. Localized hypertrophic neuropathy: possible focal perineurial barrier defect. Acta Neuropathol (Berl)
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Sciacco M, Scarpini E, Baron PL, Doronzo R, Moggio M, Passerini D, et al. Sural nerve immunoreactivity for nerve growth factor receptor in a case of localized hypertrophic neuropathy. Acta
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Mitsumoto H, Estes ML, Wilbourn AJ, Culver JE. Perineurial
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Izumi T, Kusaka H, Imai T. A case of localized hypertrophic neuropathy in the sciatic nerve. Rinsho Shinkeigaku 1995;35:38-43.
Taras J, Melone CP. Hypertrophic neuropathy presenting with ulnar nerve compression: a case report. J Hand Surg Am
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Simmons Z, Mahadeen ZI, Kothari MJ, Powers S, Wise S, Towfighi J. Localized hypertrophic neuropathy: magnetic resonance
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49
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V-5B. Soft tissue perineurioma/extraneural perineurioma
Soft tissue perineurioma (STPN) is the term coined for
a soft tissue tumor composed of cells showing perineurial differentiation. According to Lazarus and Trombetta 1, who first reported the entity in 1978, STPN represented a third category of peripheral nerve sheath tumors alongwith schwannoma and neurofibroma. Subsequently, the terms storiform perineurial fibroma and
extraneural perineurioma (EPN) have also been used
interchangeably to describe this lesion (see above at the
Background section).
A computerized bibliography search (pubmed) from
1978 to the end of 2004 year revealed 144 cases of benign STP/EPN in the literature 1-50, albeit not all fully
documented. In the critical review of Giannini et al. 18,
up to 1997, only 13 cases were considered genuine
STP/EPN out of 22 cases since reported as such.
CLINICAL FINDINGS
STPN/EPN usually presents as a well circumscribed
soft tissue tumor mass, arising mainly in the subcutaneous tissues or subfascial planes of limbs and trunk of
young and adult individuals, which unlike IPN is not
associated with a peripheral nerve, even though it may
occasionaly lie adjacent to it. Both sexes are affected,
predominantly females (female to male ratio around
2:1). Patients are usually adult (median age around 45
years), but pediatric cases are also on record 1 7 17 44.
STP/EPN usually occur in the skin 22 24 32 33 48 as well as
in superficial and deep somatic soft tissue 9 13 18 22 50.
However, intraoral (case 2 of a series of 6) 35 43, paranasal intrasinusal 18, intraosseous 3 41, retroperitoneal soft
tissue 44, and visceral locations have also been observed. Visceral locations of STPN/EPN have been mainly
renal both in childhood 17 26, occasioning the clinically
difficult differential diagnosis of Wilms’ tumor 17, and
also adulthood 12 39. A unique intraventricular case in
the central nervous system is on record, having histological, immunophenotypical and ultrastructural similarities to the soft tissue analogues 27. Symptoms are mass
related. No motor-sensory disturbances have been recorded. Most STPN/EPN are less than 4 cm in size,
with a range from 3 mm 13 50 to several cm, including a
giant form of 20 cm 16. Acral sites, mainly hands and digits 22 25 37 38 44 45 48, are often involved, and one case involved the hands bilaterally 38. The face is uncommonly
involved 34 47. Almost unique occurrences are those in
the breast 8, external auditory canal 20, and external male genitalia 30 40.
PATHOLOGICAL FEATURES
Grossly the tumor is well-circumscribed but unencapsulated. The consistency varies from rubbery and firm
to soft. On cut surface the color is whitish to grey. Some examples, particularly the renal forms, are myxoid.
Histologically several types of STPN/EPN have been
described 50. The case of Lazarus and Trombetta 1 still
remains the prototype of the conventional form 9 13 18.
Subsequently striking microscopical variations have
been reported of this tumor, such as the fibrous/sclerosing 22 24 33 38 45 (Fig. V-5Bi), myxoid 6 7 10 12, pacinian-like
31
, sclerosing pacinian-like 36, retiform or reticular 5 28 35,
plexiform 11 31, epithelioid 32 and lipomatous 46. Transitional or combined forms may be apparent as well.
The conventional form consists of spindle or elongated
cells, often arranged in parallel or as intersecting fascicles with occasional storiform arrangements. Fibrous,
hyalinizing or myxoid changes of stroma may occur.
Distinctive cellular arrangements include tactile-corpuscle-like structures and pseudo-onion bulb or Verocaylike body arrangements. The prominence of any of these latter histological aspects allows the qualification of
some of the aforementioned variants. Psammomatous
calcifications are seen only occasionally 9 and metaplastic ossification has been seen only once 23.
Some histological subtypes are more often seen in peculiar locations, such as the sclerosing variant in the
hands and digits 22 31 45 and the pacinian-like variant in
the digits 31 36. A unique case of STPN/EPN with granular cell changes has also been described 21 and one case
of sclerosing perineurioma with prominent collagen rosettes has also been observed 50. The retiform and the
plexiform variants were so termed, following the architectural pattern of the tumor growth, while the lipomatous variant contains an adipose tissue component.
Finally, hybrid or composite forms with histological
and immunophenotypical features of both STP/EPN
and schwannoma 50-52 as well as STPN/EPN and neurofibroma 52 53 have recently been reported in extradigital
and digital locations.
Atypical forms 54 55 and malignant examples of STPN/EPN have been occasionally encountered 56-62, identified by cellularity and nuclear atypia in the former category, and additionally by mitoses and necrosis in the
latter.
IMMUNOHISTOCHEMISTRY AND ELECTRON
MICROSCOPY
Immunohistochemically STPN/EPN is – like its intraneural counterpart – vimentin and EMA positive (Fig.
TUMORAL, QUASITUMORAL AND PSEUDOTUMORAL LESIONS OF SOFT TISSUE
V-5Bii) and negative for S-100 protein, CD57, synapthophysin, desmin, actins, FXIIIa). CD34 is usually
negative, but may be focally positive in some cases 35 50
or even occasionally diffusely positive 37. Collagen IV
is sufficiently detectable in a pericellular distribution,
but laminin is weakly expressed 50. New adjunctive immunomarkers include claudin-1 42, a member of the
protein family involved in the formation of tight intercellular junctions, and GLUT1 45, the human erythrocyte glucose transporter antigen.
Ultrastructurally STPN/EPN is mainly or solely composed of cells showing perineurial differentiation, i.e., slender cytoplasmic processes coated by a discontinuous external lamina, tight junctions uniting the ends of cell processes, few cytoplasmic organelles, vimentin filaments,
and numerous pinocytotic vesicles 63 (Figs. V-5Biiii, V5Biv). Many authors employed electron microscopy in
the study of their cases 1 4-23 27 31 35 41 44 45 50. In two cases ribosome-lamella complexes have been seen 15 50. These
have also been described in another ST tumor, the ossifying fibromyxoid tumor, a neoplasm which is also
suggested to exhibit neural differentiation 64.
Immunohistochemistry and electron microscopy serve
as essential tools also for the diagnosis of STPN/EPN,
and both immunohistochemistry and ultrastructural findings are – as previously said – similar to those observed in IPN.
SPECIAL STUDIES
FISH analysis demonstrated an abnormality of chromosome 22 even in STPN/EPN 18 36, similarly to what
was previously described in INP/LHN, a fact that “supports” the view that both STPN/EPN and INP/LHN are
part of the spectrum of perineurial neoplasia 18. Clonal
chromosomal abnormalities of chromosome 10 and a
cryptic deletion of the 5’BCR and NF2 loci on chromosome 22 were found in a cytogenetic and molecular
study 29.
DIFFERENTIAL DIAGNOSIS
Many diverse tumors enter the differential diagnosis, in
accordance with the numerous histological types of STPN/EPN.
The conventional type is to be distinguished from a
wide spectrum of spindle cell tumors and tumor-like
lesions, including neurofibroma, schwannoma, solitary encapsulated neuroma 65 , neuroblastoma-like
neurilemmoma 66 , neuroblastoma-like epithelioid
schwannoma 67, dermatofibroma, nodular fasciitis,
nerve sheath myxoma, tendon sheath fibroma, subcutaneous fibrous meningioma, dermatofibrosarcoma
protuberans, solitary fibrous tumor, myoepitheliomas
68 69
, low grade myofibrosarcoma 70 71, low grade peripheral nerve sheath tumor, and monophasic synovial
sarcoma.
The fibrous or sclerosing (also called hypocellular or
collagenized form) needs to be differentiated from fibroma-NOS, desmoid tumor, desmoplastic fibroblastoma (collagenous fibroma) 72, circumscribed storiform
103
collagenoma (sclerotic fibroma) 73 and solitary fibrous
tumor (hypocellular variant).
The myxoid form needs to be distinguished from lowgrade myxofibrosarcoma, low grade fibromyxoid sarcoma, and myxoid dermatofibrosarcoma protuberans.
The pacinian-like variant of STPN/EPN, usually occurring in superficial sites of the hands and digits, is considered by some authors 31 63 as the same entity as the
pacinian neurofibroma of the older literature 74-77.
The plexiform variant, which is also commonly
myxoid, must be differentiated from neurothekeoma,
and in fact some examples of the latter probably represent misdiagnosed cases of STP/EPN of the plexiform
type 78-80 The retiform or reticular form has an architectural pattern mimicking ossifying fibromyxoid tumor 81
and extraskeletal myxoid chondrosarcoma 82, which
need to be excluded.
The lipomatous perineurioma should be considered in
the differential diagnosis of both spindle cell mesenchymal and neuroectodermal tumors that contain an
adipocytic component, such as spindle cell lipoma and
spindle cell liposarcoma among the former, and lipomatous neurofibroma among the latter 83 84.
However, the correct diagnosis rests foremost on awareness of this entity, which – despite its protean, histological appearances, has a remarkably constant immunoprofile and ultrastructural appearance. Practically none of the differential diagnostic considerations listed
above has such a simple immunoprofile, except for the
rare occurrence of a fibrous or transitional type of ordinary meningioma, which may be encountered especially in the head and neck area as an heterotopic event or
as a transosseous penetration from a meningeal based
tumor. In this latter situation, electron microscopy can
ascertain the meningotheliomatous differentiation by
showing complexly interdigitating processes, intercellular desmosomes, lack of pinocytotic vesicles, abundant intermediate filaments and lack of external lamina.
However caution must be exercised since several tumor-like conditions and genuine tumors in the schwannoma/neurofibroma spectrum may express EMA in a
proportion of cells, the latter interpreted as reactive 1 2 3
5
. Neurofibroma might be the most likely diagnostic pitfall, due to the participation not only of several distinct
cell types in this tumor, i.e., Schwann cells, perineurial
cells, and fibroblasts, but also of intermediate cells, having overlapping ultrastructural and immunophenotypical features, i.e., hybrid Schwann-perineurial cells and
fibroblast-perineurial cells 63. Some neurofibromas do
exhibit a predominantly ultrastructural perineurial cell
differentiation 85 or show a prominent immunohistochemical perineurial cell component 54. There is a case published as a perineurioma 11, comprehensively studied
by multiple modalities, which was excluded as a perineurioma after critical revision by others, who interpreted the tumor as a likely perineurial cell-rich neurofibroma 18. A further case is on record which was interpreted as a likely perineurial cell-rich neurofibroma by
its authors, which showed the typical immunoprofile of
M. BISCEGLIA, ET AL.
104
Schwann cells on one hand and ultrastructural features
of perineurial cells on the other 86.
Ultimately, STPN/EPN may also enter the differential
diagnosis of dendritic cell neurofibroma with pseudorosettes 87 88, the latest described variant in the neurofibroma spectrum, of which even an intraneural subtype 89
has also been recognized: however, dendritic cell neurofibroma with pseudorosettes is S-100 protein positive
(and EMA negative) and is typified by pseudorosettes,
which are absent in STPN/EPN.
BIOLOGICAL BEHAVIOUR
Ordinary STPN/EPN in its various morphological guises is a benign tumor. However, few atypical (cellular)
examples have been seen, the behaviour of which has
not been established yet 54 56. Further, examples of both
histologically and clinically malignant cases have also
been described 57-62.
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V-6. Superficial (cutaneous and subcutaneous) Ewing’s sarcoma
Ewing’s sarcoma is primarily an undifferentiated small
round cell tumor of bone, representing in order of frequency the fourth neoplasm in this location, after myeloma, osteosarcoma, and chondrosarcoma in general
and the second most common primary osseous malignancy in childhood and adolescence after osteosarcoma. Ewing’s sarcoma also occurs (10% of cases) as a
primary tumor in soft tissue without involvement of
bone (primary extraosseous Ewing’s sarcoma).
Ewing’s sarcoma and peripheral primitive neuroectodermal tumor (EWS/pPNET), including primitive neuroepithelioma, are neoplasms of the same family
(Ewing family of tumors), the former tumor without
and the latter with neural differentiation. EWS/pPNET
comprises around 1% of soft tissue tumors in general;
the most common location are the deep soft tissues of
the lower extremities (including the periosteal tissue),
the paravertebral region, the retroperitoneum, and the
intraabdominal cavity (pelvis, peritoneum, diaphragm). Rare visceral locations are also on record (kidney, pancreas, uterus, larynx). Very rarely it occurs in
the skin and subcutaneous tissues (superficial
EWS/pPNET) with forty-five cases of primaries reported so far 1-17. The first report of three cases is due to
Angerwall and Enzinger and dates back to 1975 1. Up
to 1995 all cases were studied by light microscopy alone, with the only support of electron microscopy in some. In the years 1995-1997, cutaneous and subcutaneous EWS/pPNET were published, which were additionally studied by immunohistochemistry 11-13, and in
1998 the first cases corroborated by molecular genetic
investigations also appeared 14. From all these investigative techniques documentation derived that superficial EWS/pPNET has the same morphology, immunophenotype and molecular abnormalities as seen in
bone and deep soft tissue counterparts.
CLINICAL FINDINGS
Children and young people are usually affected 13 14 16,
but less often superficial EWS/pPNET also occurs in
adulthood with six such total cases on record 1 4 7-9 13 17.
Congenital cases may also be encountered (MB, unpublished personal observation of two cases). Both sexes
are affected. In order of frequency, anatomic locations
include lower limbs, trunk (chest and abdomen) and
pelvis, head (mainly the scalp) and neck, and upper
limbs 13 14 17. A case of EWS/pPNET of the breast is also on record 18. The main sign in cutaneous and subcutaneous locations is represented by a solitary nodular
lesion, sometimes with polypoid appearance, often clinically misinterpred as an adnexal skin tumor or even a
trivial lesion (hemangioma, pyogenic granuloma, dermoid or trichilemmal cyst). In none of the published
cases of superficial EWS/pPNET, evidence of tumor at
other locations was found.
PATHOLOGICAL FEATURES
Grossly, the tumor is most often described as a solid,
well circumscribed, but unencapsulated, nodular mass,
ranging in size 1 to 10 cm. On cut section it is described as a greyish-white and fleshy nodule. Foci of hemorrhage are often visible. Histologically, the growth
pattern may be compact as well as retiform (due to dyscohesion of cells), or microcystic or frankly pseudocystic. Rosettes of the Flexner-Wintersteiner type
have been seen in one unique case of congenital superficial EWS/pPNET (personal unpublished observation
of one (MB) of the authors). The tumor is composed by
undifferentiated small round cells, with scanty to moderate glycogen-rich cytoplasm, and vesicular nuclei,
with few to many mitoses Fig. V-6i→V-6iii.
IMMUNOHISTOCHEMISTRY
Immunohistochemically, tumor cells in superficial
EWS/pPNET are usually positive for vimentin. Occa-
TUMORAL, QUASITUMORAL AND PSEUDOTUMORAL LESIONS OF SOFT TISSUE
sionally, rare cells may express cytokeratins. Muscle
markers are negative, but desmin has been seen as a divergent expression in one study 13 and interpreted as an
indication of an overlapping phenotypic spectrum with
(intraabdominal) desmoplastic small cell tumor, but was
not confirmed in another 14; all endothelial markers are
always negative as negative are lymphoid and myeloid
markers. Some neural/neuroendocrine markers (including S100-protein, NSE, neurofilament proteins,
PGP9.5, synapthophysin, and Leu-7) have been found
positive by some authors 13, but could not be confirmed
by others, except NSE 14. In the latter report chromogranin was tested in one case only, and was also negative.
For reference and comparison we would like to quote
the results of an immunohistochemical study of 28 total cases 19 performed on osseous (19 cases) and soft
tissue (9 cases) EWS/pPNET: NSE was found in 17 cases, S-100 protein in 7, Leu-7 in 4 and neurofilament
proteins in 2, while chromogranin was never detected;
and the investigators of the last study – according to the
expression of the number of neural markers – categorized their cases in a three-tiered classification scheme of
undifferentiated (no marker positive: 10 cases), poorly
differentiated (1 marker positive: 12 cases) and well
differentiated (2 markers positive: 4 cases) tumors.
In all studies, similarly to their bone and deep soft tissue counterparts, practically all cases of superficial
EWS/pPNET 13 14 17 were positive for CD99/MIC2 antigen, the protein product p30/32 of the MIC2 gene, and
the most reliable marker in defining EWS/pPNET diagnosis (Fig. V-6iv).
ELECTRON MICROSCOPY
Ultrastructurally 13 20, in EWS/pPNET the tumor cells
are small with high nuclear to cytoplasmic ratio. The
cytoplasm is organelle-poor with visible intermediate
filaments of vimentin type. Glycogen is usually abundant either in pools or in dispersed particles. Neuroendocrine granules can often be observed (5 positive cases out of 7 studied in the report by Banerjee et al. 13),
while microtubules are vanishingly rare (1 positive case out of 7). Nuclei are round with dispersed chromatin
and small nucleoli. Cytoplasmic projections may be
seen as are primitive intercellular junctions. Synaptic
junctions have been documented in 1 case as well.
For comparison, in the previously referenced study 19,
which also classified osseus and extraosseous
EWS/pPNETs according to three categories on the basis of the number of positive ultrastructural findings
(neurosecretory granules and/or cytoplasmic processes), 8 tumors were undifferentiated, 14 poorly differentiated (expressing either neurosecretory granules in
8 or cytoplasmic processes in 6), and 4 well-differentiated (expressing both). Interestingly, the poorly differentiated tumors predominated among the osseous
forms, while the reverse occurred among the well-differentiated. No other specific specialized substructure
has been ever found in EWS/pPNET of any location,
such as myofilaments, sarcomeres, melanosomes.
107
SPECIAL STUDIES
In EWS/pPNET of classical osseous and extraosseous
sites, a specific genetic translocation may be demonstrated by molecular investigation, using usual cytogenetic technique as well as reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) techniques. A translocation at
t(11;22) (q24;q12), fusing FLI1 and EW genes, can be
identified in up to 85% of cases by usual cytogenetics
and in up to 90% by RT-PCR. In approximately 9% of
ES/pPNETs a variant translocation t(21;22) (q22;q12),
fusing ERG and EWS genes, is detectable, in absence
of the former. Concerning with cytogenetic translocation in superficial EWS/pPNET in all cases so far tested, FISH analysis was used for this purpose and was
always positive 14.
Anyway other types of translocations not involving the
classical chromosome region 22q12 have been found in
superficial EWS/pPNETs 21 22: these latter cases showed
a highly aggressive course with hematogenous metastases. For a review of the genetic abnormalities in
EWS/pPNET of the common sites the reader is referred
to other sources 23.
DIFFERENTIAL DIAGNOSIS
As a member of the “small round-cell tumor” family
the differential diagnosis of EWS/pPNET include a large variety of neoplasms, primary or secondarily involving the skin, of different lineages.
In childhood mainly a metastatic involvement by peripheral neuroblastoma (“classic-type”), rhabdomyosarcoma (alveolar or embryonal types), or lymphoma and
leukemia (including granulocytic sarcoma) should be
considered. In one of the two congenital cases, we already mentioned, which was seen by several consultants,
the differential diagnosis included among others also synovial sarcoma and infantile hemangiopericytoma. In
adulthood, classically, metastatic undifferentiated or
neuroendocrine small cell carcinoma along with primary
cutaneous neuroendocrine carcinoma (Merkel cell tumor) and small cell amelanotic melanoma are the priorities; atypical glomus tumor and glomangiosarcoma might also be a possibility of consideration in differential.
Noteworthily, we would like to emphasize the morphological resemblance of cutaneous and subcutaneous
EWS/pPNET to some benign and malignant adnexal
skin tumors, such as eccrine spiradenoma 17, because of
the comprising small cells, vascularity and pseudocystic
spaces: a highly misleading similarity which has been already brought to light by other authors 13.
However, if immunohistochemistry is used, a confident
diagnosis is reached because of the lack in EWS/pPNET
of the main and specific immunohistochemical findings,
which are usually present in the alternative diagnostic
considerations, and conversely by virtue of the high sensitivity and good specificity of the CD99 expression in
EWS/pPNET 24. However, CD99 expression can also be
found in other tumors, including lymphoblastic lymphoma, rhabdomyosarcoma, neuroendocrine tumors, and
M. BISCEGLIA, ET AL.
108
synovial sarcoma, all neoplasms which enter the differential diangosis with EWS/pPNET.
Peripheral neuroblastoma metastatic to skin may be very
challenging both histologically and immunohistochemically. In dubious cases electron microscopy and molecular analyses (FISH testing as well as RT-PCR) can solve
the problem by detecting the specific genetic aberrations.
The clinicopathologic setting in these instances should
also be helpful and in accordance with the histological
diagnosis, bearing in mind that EWS/pPNET is consistently a localized disease. Cutaneous and subcutaneous
EWS/pPNET may also represent a metastatic seeding
from bone or deep seated primary is even possible 25.
Awareness of this unusual location of EWS/pPNET is
mandatory for general surgical pathologyst since this
form of the disease may well occur in routine practice.
Awareness may let the pathologist suspect the tumor
and address to the correct diagnosis which can be definitely established even at the light and immunohistochemical level.
BIOLOGICAL BEHAVIOUR
Superficial
(cutaneous
and
subcutaneous)
EWS/pPNET is believed to be a favourable subset 14 16
of an otherwise highly aggressive neoplasm, and there’s some slight evidence that superficial EWS/pPNET
represents the more differentiated end of the spectrum
(high rate of presence of neuroendocrine granules, evidence of microtubules, documented synaptic junctions
and synaptophysin expression in some of the cases in
the study of Banerjee et al. 13).
With the exceptions of those two cases 21 22, which
showed a genetic translocation not involving the chromosome region 22q12, in none of the remaining cases a
multisystemic spread has been found, and this may be the
main reason for the good prognosis, since initial presentation has been demonstrated as the only predictor of survival in soft tissue EWS/pPNET in general 26. Local surgical excision followed by local radiotherapy and courses
of systemic chemotherapy is the suggested multimodal
treatment in this usually apparently localized disease 16.
References
(In refs. 1-17 the actual number of cases of superficial EWS/pPNET
per report is indicated in brackets).
1
Angerwall L, Enzinger FM. Extraskeletal neoplasm resembling
Ewing’s sarcoma. Cancer 1975;36:240-51(3 cases).
2
Hashimoto H, Enjoji M, Nakajima T, Kiryu H, Daimaru Y. Malignant neuroepithelioma (peripheral neuroblastoma). A clinicopathologic study of 15 cases. Am J Surg Pathol 1983;7:309-18(1
case).
3
Peters MS, Reiman HM, Muller SA. Cutaneous extraskeletal
Ewing’s sarcoma. J Cutan Pathol 1985;12:476-85(1 case).
4
Argenyi ZB, Bergfeld WF, McMahon JT, Goeken JA, Garewal
GS. Primitive neuroectodermal tumor in the skin with features of
neuroblastoma in an adult patient. J Cut Pathol 1986;13:42030(1 case).
5
Patterson JW, Maygarden SJ. Extraskeletal Ewing’s sarcoma with
cutaneous involvement. J Cutan Pathol 1986;13:46-58(1 case).
6
Smolle-Juettner FM, Smolle J, Richtig E, Kraus I, Popper H,
Becker H. Primitive neuroectodermal tumor arising in the skin.
Differentiation from neuroendocrine carcinomaof the skin. Dermatology 1992;185:272-5(1 case).
7
Swanson PE, Jaszcz W, Nakhleh RE, Kelly DR, Dehner LP. Peripheral primitive neuroectodermal tumors: a flow cytometric
analysis with immunohistochemical and ultrastructural observations. Arch Pathol Lab Med 1992;116:1202-8(1 case).
8
Nguyen AV, Argenyi ZB. Cutaneous neuroblastoma: peripheral
neuroblastoma. Am J Dermatopathol 1993;15:7-14(1 case).
9
Sangueza OP, Sangueza P, Valda LR, Meshul CK, Requena L.
Multiple primitive neuroectodermal tumors. J Am Acad Dermatol
1994;31:56-361(1 case).
10
Perlman EJ, Lumadue JA, Hawkins AL, Cohen K, Colombani P,
Griffin CA. Primary cutaneous neuroendocrine tumors. Diagnostic use of cytogenetics and MIC2 analysis. Cancer Genet Cytogenet 1995;82:30-4(1 case).
11
Lee CS, Southey MC, Slater H, Auldist AW, Chow CW, Venter
DJ. Primary cutaneous Ewing’s sarcoma/peripheral primitive
neuroectodermal tumors in childhood. A molecular, cytogenetic,
and immunohistochemical study. Diagnost Mol Pathol
1995;4:174-81(2 cases).
12
Sexton CW, White WL. Primary cutaneous Ewing’s family sar-
13
14
15
16
17
18
19
20
21
22
23
coma. Report of a case with immunostaining for glycoprotein
p30/32 mic2. Am J Dermatopathol 1996;18:601-5(1 case).
Banerjee SS, Agbamu DA, Eyden BP, Harris M. Clinicopathological characteristics of peripheral primitive neuroectodermal tumor of skin and subcutaneous tissue. Histopathology
1997;31:355-66(8 cases).
Hasegawa SL, Davison JM, Rutten A, Fletcher JA, Fletcher
CDM. Primary cutaneous Ewing’s sarcoma. Immunophenotypic
and molecular cytogenetic evaluation of five cases. Am J Surg
Pathol 1998;22:310-8(5 cases plus one in addendum).
Chao TK, Chang YL, Sheen TS. Extraskeletal Ewing’s sarcoma
of the scalp. J Laryngol Otol 2000;114:73-5(1 caso).
Chow E, Merchant TE, Pappo A, Jenkins JJ, Shah AB, Kun LE.
Cutaneous and subcutaneous Ewing’s sarcoma: an indolent disease. Int J Radiat Oncol Biol Phys 2000:46:433-8(14 casi).
Pericotti S, Parma A, Bisceglia M, Pasquinelli G. Sarcoma di
Ewing, primitivo della cute. Presentazione di un caso. G Ital Dermatol Venereol 2003;138:192-4(1 case).
Sezer O, Jugovic D, Blohmer JU, Turzynski A, Thiel G, Langelotz C, et al. CD99 positivity and EWS-FLI1 gene rearrangement
identify a breast tumor in a 60-year-old patient with attributes of
the Ewing family of neoplasms. Diagn Mol Pathol 1999;8:120-4.
Franchi A, Pasquinelli G, Cenacchi G, Della Rocca C, Gambini
C, Bisceglia M, et al. Immunohistochemical and ultrastructural
investigation of neural differentiation in Ewing sarcoma/PNET of
bone and soft tissues. Ultrastruct Pathol 2001;25:219-25.
Pearson JM, Harris M, Eyden BP, Bnerjee SS. Divergent differentiation in small round-cell tumors of the soft tissues with neural features – an analysis of 10 cases. Histopathology 1993;23:19.
Somers GR, Shago M, Zielenska M, Chan HS, Ngan BY. Primary
subcutaneous primitive neuroectodermal tumor with aggressive
behavior and an unusual karyotype: case report. Pediatr Dev
Pathol 2004;7:538-45.
Llombart-Bosch A, Pellin A, Carda C, Noguera R, Navarro S,
Peydro-Olaya A. Soft tissue Ewing sarcoma – peripheral primitive neuroectodermal tumor with atypical clear cell pattern shows
a new type of EWS-FEV fusion transcript. Diagn Mol Pathol
2000;9:137-44.
Sandberg AA, Bridge JA. Updates on cytogenetics and molecular
genetics of bone and soft tissue tumors: Ewing sarcoma and pe-
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24
25
ripheral primitive neuroectodermal tumors. Cancer Genet Cytogenet 2000;123:1-26.
Devoe K, Weidner N. Immunohistochemistry of small round-cell
tumors. Semin Diagn Pathol 2000;17:216-24.
Izquierdo MJ, Pastor MA, Carrasco L, Requena C, Farina MC,
26
Martin L, et al. Cutaneous metastases from Ewing’s sarcoma: report of two cases. Clin Exp Dermatol 2002;27:123-8.
Martin RC 2nd, Brennan MF. Adult soft tissue Ewing sarcoma or
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Surg 2003;138:281-5.
M. BISCEGLIA, ET AL.
110
V-1. Psammomatous melanotic schwannoma
Fig. V-1i. Spindled cells arranged in cellular whorls characterize
this psammomatous melanotic schwannoma. Note the focal
psammoma bodies on the right.
Fig. V-1ii. Psammomatous melanotic schwannoma with epithelioid cells arranged in lobules. Note the lymphocytes between
tumor lobules. Psammoma bodies were sparse in this example.
Fig. V-1iii. Coarse melanin pigment in tumor cells and histiocytes.
Fig. V-1iv. Spherical to oval laminated calcospherites (psammoma bodies) range from a few to many.
V-2. Pigmented neurofibroma
Fig. V-2i. Some areas of pigmented neurofibroma can be hypercellular.
Fig. V-2ii. Wagner-Meissner bodies may be a prominent feature
of pigmented neurofibroma.
111
TUMORAL, QUASITUMORAL AND PSEUDOTUMORAL LESIONS OF SOFT TISSUE
Fig. V-2iii. Pigmented cells often have a morphology of bipolar
dendritic cells.
Fig. V-2iv. Masson-Fontana silver impregnation method reveal
cells with coarse pigmentation; the pigmentation may be only
dust-like (left side of the picture).
V.3. Dendritic cell neurofibroma with pseudorosettes
Fig. V-3i. Dendritic cell neurofibroma with pseudorosettes: multiple pseudorosettes are the hallmark of the lesion.
Fig. V-3ii. Dendritic cell neurofibroma with pseudorosettes: a
close-up view of pseudorosettes. Small, dark, lymphocyte-like
cells (Type I cells) are arranged concentrically around larger cells,
with pale-staining vesicular nuclei and copious faintly eosinophilic cytoplasm (Type II cells). Stellate extensions may be discerned
in the cytoplasm of some of the type II cells.
Fig. V-3iii. Dendritic cell neurofibroma with pseudorosettes:
pseudorosettes are often grouped within a lesion. Inset: scrolllike structure.
Fig. V-3iv. Intraneural dendritic cell neurofibroma with pseudorosettes: this tumor occurred almost entirely within the confines
of the perineurium.
M. BISCEGLIA, ET AL.
112
Fig.V-3v. Intraneural dendritic cell neurofibroma with pseudorosettes: EMA stains the perineurium that encircles the neoplasm.
Fig. V-3vi. Dendritic cell neurofibroma with pseudorosettes:
slender dendritic extensions of the cytoplasm of the type II cells highlighted by S-100 protein. Note a spider-like appearance of
these cells.
V-4. Epithelial Sheath neuroma
(The pictures are courtesy of T. Mentzel, M.D., and H. Kutzner, M.D., both Dept. of Dermatophatology, Friedrichshafen, Germany).
Fig. V-4i. Epithelial sheath neuroma: the superficial dermis contains several enlarged bundles of mature peripheral nerves surrounded by an epithelial sheath.
Fig. V-4ii. Epithelial sheath neuroma: the epithelial sheath is
composed of squamous epithelium, with focal keratinization.
Fig. V-4iii. Epithelial sheath neuroma: a sparse infiltrate of
lymphocytes and plasma cells is present around some of the
neuroepithelial aggregations.
Fig. V-4iv. Epithelial sheath neuroma: perineural epithelial
sheaths are cytokeratin positive.
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TUMORAL, QUASITUMORAL AND PSEUDOTUMORAL LESIONS OF SOFT TISSUE
V-5A. Intraneural perineurioma/localized hypertrophic neuropathy
Fig. V-5Ai. Rope-like tumoral enlargement of left ulnar nerve.
Notice the secondary (neurogenic) muscle atrophy of the hypothenar eminence. The pictures are courtesy of E. Vigilante, M.D.,
Dept. of Orthopedics, Casa Sollievo della Sofferenza Hospital, S. Giovanni Rotondo, Italy.
Fig.V-5Aii. Fascicular biopsy of the (ulnar) nerve. Histologic picture. Numerous intraneural pseudo-onion bulbs made of perineurial cells, with collagen deposition. Inset: immunohistochemical positive stain for EMA. Axonal loss was also documented by
immunohistochemical stain for neurofilament proteins (not
shown).
Fig. V-5Aiii. Layers of spindle cells with tracts of external laminalike material. Numerous pinocytotic vesicles are evident along
the cytoplasmic processes of perineurial cells (arrows).
Fig. V-5iv. Higher magnification. Subplasmalemmal rows of pinocytotic vesicles are well visible.
V-5B. Soft tissue perineurioma/extraneural perineurioma
Fig. V-5Bi. Histology. Fibrous tumor mainly composed of slender spindle cells embedded in abundant collagen matrix.
Fig.V-5Bii. Immunohistochemical diffuse positive stain for EMA
highlighting the long and thin innumerable cytoplasmic processes in the collagenized tumor background.
M. BISCEGLIA, ET AL.
114
Fig. V-5Biii. Ultrastructural detail of a tumor spindle cell showing
an external lamina and numerous subplasmalemmal micropinocytotic vesicles (arrows).
Fig. V-5Biv. A thin cytoplasmic process surrounded ensheated
on both sides by basal lamina and showing several pinocytotic
vesicles, partly scattered and partly in clusters.
V-6. Superficial (cutaneous and subcutaneous) Ewing’s sarcoma
Fig. V-6ii. High power. Same lesion as the previous figure. Hypercellular tumor comprised of small and round cells with scanty
cytoplasm. Nuclei have dispersed chromatin. A mitotic figure visible in the center.
Fig. V-6i. Low power of
a small round-cell tumor involving the dermis and the subcutis of
the inguinal region in
an old patient aged 64.
Fig. V-6iii. PAS preparation. Tumor cells have diffusely glycogenrich cytoplasm.
Fig. V-6iv. Immunohistochemical testing for CD99/MIC2 antigen.
This case was also studied by electron microscopy which showed
ultrastructural findings consistent with EWS/pPNET.