An Update On Cutaneous Tumours With Neural Differentiation

MINI-SYMPOSIUM: CUTANEOUS SOFT TISSUE TUMOURS
An update on cutaneous Histological features

Distinctive morphological features of the entity are multiple hy-
tumours with neural perplastic enlarged peripheral nerves composed of axons,

Schwann cells and perineurial cells in the superficial dermis,
differentiation ensheathed by mature stratified squamous epithelium replacing

the perineural spaces (Figure 1).1,2 The nerves in the central
aspects of the proliferation are most commonly involved with
Bo
stjan Luzar circumferential ensheathment by stratified squamous epithelium.

Daja Sekoranja At the periphery, ensheathment of the nerves is often incomplete
or absent.1 The stratified squamous epithelium lacks atypia as a
rule and mitotic activity is usually absent. In addition, a granular
Abstract layer is often present and covered by orthokeratotic basket
weave keratin.1 Scattered dyskeratotic cells and squamous
Cutaneous peripheral nerve sheath tumours are diverse proliferations
eddies can occasionally be seen.1 Neuroepithelial aggregates are
of neuroectodermal origin ranging from benign, atypical to clearly ma-
often surrounded by sparse lymphoplasmacytic infiltrate, loose
lignant. In this update we review the clinico-pathological features sup-
myxoid stroma and mild fibrosis.
plemented by recent molecular genetic data of a variety of peripheral
nerve sheath tumours arising primarily in the skin, including epithelial
Immunohistochemical features
sheath neuroma, nerve sheath myxoma, schwannoma variants, neuro-
The hyperplastic and thickened peripheral nerves show consis-
fibroma variants, hybrid tumours, perineurioma, malignant melanotic
tent positivity for S100 protein, neurofilament, CD57 and nerve
schwannian tumour and malignant peripheral nerve sheath tumour
growth factor receptor.1 The peripheral epithelial sheath gener-
(classical and epithelioid). Particular emphasis is also given to the dif-
ally demonstrates strong positivity for CK-MNF116, less intense
ferential diagnosis of these proliferations.
positivity for CK-AE1/AE3 and is consistently negative for CEA
Keywords epithelial sheath neuroma; hybrid tumours; malignant and EMA.1
melanotic schwannian tumour; neurofibroma; perineurioma; peripheral
nerve sheath tumours; schwannoma Molecular genetic features
No data exist on possible molecular genetic aberrations in
epithelial sheath neuroma to date.
Epithelial sheath neuroma
Treatment and prognosis
Introduction A complete excision of the proliferation is curative. No re-
Epithelial sheath neuroma is a term coined by Requena et al. in currences following complete excision have been reported.
2000 for a distinctive benign proliferation in the skin character-
ized histologically by increased numbers of thickened peripheral Differential diagnosis
nerves in the superficial dermis intimately associated with The main differential diagnosis is with perineural invasion by
mature stratified squamous epithelium in the perineural space of epithelial malignancy, followed by pseudo-perineural invasion at
the nerves, thereby mimicking perineural invasion by epithelial the site of previous procedure/surgery (also designated re-
malignancy.1 excision perineural invasion).3
Perineural invasion by epithelial malignancy can be distin-
Clinical features guished from epithelial sheath neuroma by atypia of the epithe-
Epithelial sheath neuroma generally presents as a solitary flesh lial component, the presence of a scar due to a previous
coloured or erythematous papule or nodule measuring from 5 to procedure and data on prior malignancy in the corresponding
20 mm in diameter (mean 11 mm).1,2 Interestingly, the only site area of the skin.3
of occurrence reported so far is on the skin of the back. Although Re-excision perineural invasion is a designation used for the
the proliferation can be asymptomatic, a significant proportion of presence of mature squamous epithelium in the perineural
the lesions are pruritic and/or painful. Epithelial sheath neuroma space(s) of normal cutaneous nerves at the site of previous
shows a female predominance (about 3:1) and typically develops excision.4 The following criteria have been proposed for re-
in elderly patients in their 7th decade of life (mean age 67 yrs, excision perineural invasion: 1) absence of perineural spread
from 49 to 86 yrs).1,2 As a rule, there is no history of previous beyond the area of previous biopsy/procedure, 2) benign
local trauma or treatment.1 In addition, the patients lack asso- appearance of perineural epithelial cells and 3) absence of re-
ciated conditions such as Multiple Endocrine Neoplasia e type sidual epithelial tumour in the vicinity of the involved nerves.4
2b or neurofibromatosis.1,2
Nerve sheath myxoma
Introduction
Bo
stjan Luzar MD PhD Institute of Pathology, Medical Faculty Originally described by Harkin and Reed in 1969 and further
University of Ljubljana, Ljubljana, Slovenia. Conflicts of interest: none delineated by Fetsch et al. in 1980, nerve sheath myxoma is a
declared. benign cutaneous nerve sheath tumour characterized by multi-

Daja Sekoranja MD Institute of Pathology, Medical Faculty University nodular proliferation of Schwann cells in abundant myxoid ma-
of Ljubljana, Ljubljana, Slovenia. Conflicts of interest: none declared. trix.5,6 In the literature, the term neurothekeoma coined by
DIAGNOSTIC HISTOPATHOLOGY 28:1 14 Ó 2021 Published by Elsevier Ltd.

Figure 1 Epithelial sheath neuroma. (a) Low power magnification depicting increased number of hypertrophic nerves in the dermis. (b) Hyper-
trophic nerves are surrounded by stratified squamous epithelium. (c) Epithelial sheath is composed of bland keratinocytes lacking atypia. Pictures
reproduced from Calonje E, Lazar AJ, Luzar B. Diagnostic Atlas of Cutaneous Mesenchymal Neoplasia, Elsevier 2020 with written permission of
the publisher.
Gallager and Helwing has been used interchangeably with nerve multinucleated cells, and cells with a ring-like morphology are
sheath myxoma.7 Importantly, however, nerve sheath myxoma often additionally present in variable proportions.5,8 The nuclear
is histogenetically not related to cellular or mixed-type neuro- pleomorphism is generally mild, and mitotic activity is absent or
thekeoma, a tumour of a putative fibroblastic/myofibroblastic very low (from 0 to 3 per 25 high power fields). Atypical mitoses
origin.5,8 The use of the term neurothekoma when referring to are absent as a rule. Focal formation of Verocay-like bodies is
nerve sheath myxoma is therefore discouraged to avoid any occasionally present.5,8
possible confusion. In addition to Schwann cells, which represent the predomi-
nant cell component, limited amounts of fibroblasts - usually
Clinical features CD34 positive isolated cells in the centre of the nodule(s), peri-
Nerve sheath myxoma typically presents as a solitary, slowly neurial cells - at the periphery of the nodule(s), a few intrale-
growing flesh coloured asymptomatic papule or nodule sional axons and mild inflammatory cell infiltrate are seen.5,8
measuring from 0.4 to 4.5 mm in diameter that may on occasion
be painful.5,8 Multifocal occurrence is exceptional.5,9 Over 85% Immunohistochemical features
of the tumours show a predilection for the extremities, in Schwann cells are diffusely and strongly positive for S100 pro-
particular hands/fingers, knee/pretibial area and ankle/foot, tein, SOX10 and low-affinity nerve growth factor receptor.5,8 In
followed by trunk and head and neck.5,8 Involvement of addition, the majority of tumours will reveal GFAP and CD57
extracutaneous sites is distinctly uncommon. There is no sex positivity. EMA highlights a layer of perineurial cells usually seen
predilection.5,8 at the periphery of the nodules. CD34 positive fibroblasts can
occasionally be noted towards the centres of the nodules. Rare
Histological features axons can be highlighted by neurofilament stain.
Cutaneous nerve sheath myxoma is characterized by unencap-
sulated nodular or multinodular proliferation in the dermis and/ Molecular genetic features
or subcutis (Figure 2).5,8 Tumour nodule(s) are of variable size, A study on 10 cases of spinal nerve sheath myxomas demon-
surrounded by a rim of compressed connective tissue. The strated the loss of 22q in 80% and loss of chromosome 19 in 30%
defining feature of the tumour is Schwann cells growing in cords, of the cases, two examples also exhibited NF2 mutation.10 A
strands and syncytial-like aggregates, embedded in copious study on differential gene expression profiles confirmed a clus-
amounts of myxoid matrix.5,8 Schwann cells most commonly tering of nerve sheath myxoma with classical schwannoma,
display a small epithelioid morphology, although spindled, clearly distinguishing nerve sheath myxoma from cellular or
stellate-shaped cells with multivacuolated cytoplasm, bland mixed type neurothekeoma.11

Figure 2 Nerve sheath myxoma. (a) An unencapsulated multilobular proliferation of Schwann cells in the background of myxoid matrix is the
distinctive feature of the entity. (b) Schwann cells grow in cords of bland spindled, epithelioid and stellate cells lacking mitotic activity. On
immunohistochemistry, tumour cells are positive for S100 protein (c) and GFAP (d).
Treatment and prognosis Cutaneous schwannoma

Complete excision is curative. Recurrences following incomplete
Introduction
or marginal excision are common and develop in about 50% of
Cutaneous schwannoma, also designated neurilemmoma, is a
cases.5,8 Multiple recurrences have also been reported, all
benign peripheral nerve sheath tumour composed of Schwann
following incomplete excision(s).
cells. Although axons were initially considered absent in
schwannomas, or present only at the periphery as entrapped
Differential diagnosis
nerve twigs, a subset of schwannomas may contain scattered
The main differential diagnoses of cutaneous nerve sheath
axons, either in the central portions of the tumour, or much more
myxoma are mixed and cellular variants of neurothekeoma, su-
infrequently, throughout the tumour.
perficial angiomyxoma and superficial acral fibromyxoma.
Mixed and cellular neurothekeoma is characterized by non- Clinical features
encapsulated lobular or multinodular proliferation in the The majority of schwannomas develop in the fourth to seventh
dermis and subcutis composed of epithelioid and/or spindled decade of life. There is no sex predilection and the site of
cells with varying proportions of myxoid stroma. In contrast to occurrence is widespread, with soft tissue of the extremities
nerve sheath myxoma, tumour cells are consistently negative for prevailing over the head and neck region, trunk and visceral
S100 protein by immunohistochemistry. organs.14 While the vast majority of cutaneous schwannomas
Superficial angiomyxoma is a poorly circumscribed prolifer- occur as sporadic, solitary and painless tumours, they may also
ation in the dermis and subcutis composed of uniform plump, develop as multiple tumours, in the setting of neurofibromatosis
stellate or spindle cells admixed with numerous small blood (types 1 and 2) and schwannomatosis.14e17
vessels embedded in a myxoid matrix.12 In addition, perivascular
aggregates of inflammatory cells, in particular neutrophils, are Histological features
often present at least focally.12 By immunohistochemistry, su- Encapsulation, distinct Antoni A and Antoni B areas, bland
perficial angiomyxoma is consistently S100 protein negative. spindle cells and vessels with often hyalinised walls are the
Superficial acral fibromyxoma has a predilection for peri- most prevalent histologic features of schwannomas (Figure 3).
ungual skin and is typically composed of CD34 positive spindled The more cellular Antoni A areas are composed of bland
and stellate cells arranged in a haphazard, loose storiform or spindle cells with tapered, elongated nuclei, prone to palisading
vaguely fascicular growth pattern.13 The lesional cells are and the formation of Verocay bodies, characterized by rows of
embedded in predominantly myxoid, myxo-collagenous or nuclear palisading separated by Schwann cell processes. Antoni
collagenous matrix.13 Superficial acral fibromyxoma is generally B areas are distinguished by abundant loose, myxoid stroma
S100 negative. with irregularly dispersed spindle and stellate cells, focal

Figure 3 Conventional schwannoma. (a) The tumour typically presents as an encapsulated nodule. (b) Antoni A areas are characterized by closely
packed spindle cells with wavy, elongated and tapering nuclei with ill-defined eosinophilic cytoplasm. Note also the formation of Verocay bodies.
(c) Antoni B areas with irregular distribution of spindle and stellate cells in abundant myxoid stroma. (d) The sharp transition from Antoni A to Antoni
B areas is depicted in this photo.
chronic inflammatory cells and often degenerative (ancient, see Differential diagnosis
below) changes.14,18 Fibrin thrombi are not uncommon. Mitotic Cutaneous conventional schwannoma closely resembles solitary
activity is generally low, with up to 4 mitoses per 10 high circumscribed neuroma (palisaded encapsulated neuroma), a
power fields. Atypical mitoses and areas of tumoral necrosis are benign tumour of middle-aged adults that, unlike schwannoma,
absent.14,18 shows a strong predilection for the face and sites of muco-cutaneous
Various morphologic patterns deviate from the above junction. Both tumours are encapsulated and composed of S100þ/
description of conventional schwannoma, giving rise to a num- EMA- Schwann cells, although a solitary circumscribed neuroma
ber of different schwannoma subtypes, i.e., ancient, plexiform, usually lacks distinctive Antoni A and Antoni B areas and often
cellular, epithelioid, microcystic/reticular and neuroblastoma- exhibits cleft like spaces between fascicles of spindle cells.
like (discussed below). Furthermore, solitary circumscribed neuroma contains innumer-
able axons, a feature not characteristic of schwannomas.
Schwannomas, conventional or any of the special morphologic Ancient schwannoma
subtypes, invariably show strong and diffuse positivity for S100
protein and SOX10, while expression of GFAP may be variable.19 Introduction
Epithelial membrane antigen (EMA) highlights only perineurial The term “ancient” schwannoma was introduced by Ackerman
cells in the capsule. The presence of axons can be highlighted by and Taylor in 1951 to describe 10 cases of thoracic schwannomas
neurofilament stain. with prominent degenerative features in their series of 48 tu-
mours.25 Similar degenerative features are also often seen in
Molecular genetic features cutaneous schwannomas. Some of the degenerative features
The most frequent genetic changes in schwannomas are loss of (e.g., cysts, haemorrhage and calcifications) may be detected
chromosome 22 and mutations in NF2, LZTR1 and SMARCB1 radiologically, but ancient schwannomas do not differ clinically
genes, all of which reside on chromosome 22.20e23 Nevertheless, from classical schwannomas in any other way.
none of these changes are specific to schwannomas and are not
used for diagnostic purposes.20e23 Histological features
All tumours are well circumscribed, encapsulated and often display
Treatment and prognosis areas of cystic degeneration and haemorrhage grossly (Figure 4).
In symptomatic cases, conservative excision is curative and re- Antoni A areas typically harbour Verocay bodies, while in Antoni B
currences are rare. Schwannomas are benign tumours with an areas, myxoid, vacuolar and even cystic degeneration, areas of
excellent prognosis. Nevertheless, exceptional cases of malignant haemorrhage, hemosiderin-laden macrophages, lymphocytic infil-
transformation have been described.24 tration and fibrosis are apparent.25 Intratumoral blood vessels are

Figure 4 Ancient schwannoma. (a) Low power magnification of an encapsulated tumour with areas of hyalinization and vascular changes. (b) Areas
of conventional schwannoma are often present in the background. (c) The tumour typically contains areas of haemorrhage with deposition of
haemosiderin pigment, fibrosis and chronic inflammation. (d) Prominent vascular hyalinization is characteristic of the entity. Note also degenerative
atypia of tumour cells.
often prominent, sometimes dilated, with fibrin thrombi, and conventional (more commonly) or a cellular histologic pheno-
characteristically display prominent hyalinisation of vessel walls.25 type (rarely, especially in infants and young children).26
Even though the tumour cells often exhibit nuclear hyperchromasia
and even marked nuclear pleomorphism, mitotic figures and tu- Clinical features
moral necrosis are typically absent.25 Plexiform schwannoma most commonly develops on the trunk,
extremities or head and neck region of young adults. Interest-
Immunohistochemical features ingly, cellular plexiform schwannomas have most often been
The immunohistochemical profile is identical to that of conven- reported as congenital tumours in infants or young children.27
tional schwannomas. Although they typically develop in superficial nerves and
generally measure less than 2 cm in diameter, larger tumours
Treatment and prognosis may involve major peripheral nerves. Occasionally, plexiform
Conservative surgical excision is the treatment of choice in schwannomas develop in the setting of neurofibromatosis type 1,
symptomatic tumours since local recurrences are exceedingly type 2 or in schwannomatosis.
rare. Although ancient schwannomas are essentially benign,
malignant transformation in ancient schwannomas has excep- Histological features
tionally been reported. Cutaneous plexiform schwannoma is characterized by multiple
nodules composed of spindled Schwann cells in the dermis and/or
Differential diagnosis subcutis, surrounded by a thin fibrous capsule or perineurium
Although degenerative cell atypia characterized by nuclear (Figure 5). Although densely cellular Antoni A areas with Verocay
hyperchromasia and sometimes marked nuclear pleomorphism bodies often predominate, Antoni B areas are also frequently
may raise concern of malignancy, tumour encapsulation, lack of present, albeit in limited amounts. Focal degenerative change may
mitotic activity and necrosis, along with consistent diffuse and be present, coupled with some degree of nuclear pleomorphism
strong immunohistochemical expression of S100 protein, gener- and small foci of necrosis are only exceptionally present. Mitotic
ally confirm the diagnosis of an ancient schwannoma. activity is similar to conventional schwannomas, with fewer than
4 mitotic figures per 10 high power fields (HPF). Importantly,
Plexiform schwannoma cellular plexiform schwannomas in infants and young children
can have increased mitotic activity of up to 30 mitoses/10 HPF.27
Introduction
Plexiform schwannoma is distinguished from other schwannoma Immunohistochemical features
variants primarily by its multinodular (i.e., plexiform) and often The immunohistochemical profile is identical to that of conven-
intraneural growth pattern. Plexiform schwannoma can exhibit a tional schwannomas.

Figure 5 Plexiform schwannoma. (a) Low power magnification reveals distinctive plexiform growth of the tumour in the dermis and subcutis. (b)
Multiple tumour nodules are seen dispersed throughout the dermis and subcutis. (c) Tumour nodules are surrounded by a thin capsule composed
of perineurial cells. Note the presence of Antoni A areas within the tumour. (d) Degenerative atypia of tumour cells is clearly apparent.
Treatment and prognosis life and have equal gender distribution. They most commonly
Conservative surgical excision is the treatment of choice, arise on extremities and trunk.15,16,21
although it can have debilitating consequences in cases of giant
tumours involving large proportions of a nerve. Recurrences are Histological features
rare and have only been described in children.27 Like conventional schwannomas, epithelioid schwannomas at
somatic sites are well circumscribed, often with a fibrous capsule
Differential diagnosis containing perineurial cells, while those at visceral sites tend not
Distinguishing plexiform schwannoma from plexiform neurofi- to be encapsulated.15,16,21 By definition, the majority of tumour
broma (NF) is of great clinical importance, since the latter can be cells are of epithelioid morphology, with round, oval or reniform
pathognomonic for neurofibromatosis type 1 and as such carries nuclei, small nucleoli and with abundant eosinophilic cytoplasm
an important risk of malignant transformation to MPNST. By (Figure 6). Occasionally, multinucleated giant cells may be
immunohistochemistry, S100 protein and EMA show different observed. Tumour cells are typically arranged in sheets, nests or
patterns of expression in the two lesions. In schwannoma, S100 trabeculae and the cellularity tends to be quite uniform
protein is diffusely and strongly positive throughout, while EMA throughout the tumour, without discernible Antoni A and Antoni
highlights perineurial cells in the fibrous capsule surrounding B areas. While most epithelioid schwannomas exhibit unilobular
tumour nodules. Neurofibromas typically display patchy S100 or multilobular growth, a plexiform growth pattern has also been
protein positivity with admixed EMA positive perineurial cells, described.15,16,28 Tumour stroma is often hyalinised, myxoid or a
CD34 positive fibroblasts and neurofilament positive axons. combination of both. Degenerative changes, including nuclear
pseudoinclusions, enlarged and hyperchromatic nuclei, peri-
vascular hyalinization, haemorrhagic and cystic areas are com-
Epithelioid schwannoma
mon, albeit focal.15,16,21 Proliferative activity is minimal,
Introduction demonstrated by a low Ki67 proliferative index (generally <1%).
The distinctive feature of epithelioid schwannoma is the pre- Mitotic activity is generally low (usually up to 1 mitosis per 10
dominance of epithelioid tumour cells, growing in cords and high power fields).15,16,21 Abnormal mitotic figures and tumour
nests.15,16,21 necrosis are not a feature of epithelioid schwannomas.15,16,21
Clinical features Immunohistochemical and molecular genetic features

The vast majority of tumours are sporadic, with only rare ex- In addition to the conventional schwannoma immunophenotype
amples reported in patients with schwannomatosis or neurofi- characterized by diffuse S100 protein and SOX10 positivity, up to
bromatosis 1. Epithelioid schwannomas have a wide age 42% of epithelioid schwannomas display loss of SMARCB1/INI1
distribution, show a predilection for adults in their 5th decade of expression.21 SMARCB1 inactivation via different mechanisms

Figure 6 Epithelioid schwannoma. (a) The entity is distinguished by a proliferation of tumour cells with epithelioid morphology. (b) Tumour cells
display mild to moderate nuclear atypia. Nucleoli are absent or not prominent. (c) While regular mitoses are not uncommon, atypical mitotic activity
is absent. (d) The tumour cells are diffusely positive for SOX10.
has been demonstrated in a subset of epithelioid schwannomas schwannomatosis. Although they often present as an asymp-
with SMARCB1/INI1 loss and this seems to be an early genetic tomatic mass near the vertebral column (especially in the
event shared by epithelioid schwannoma and epithelioid MPNST mediastinum, retroperitoneum or the pelvis), some tumours
with SMARCB1/INI1 loss.22 cause bone disruption and erosion leading to pain in the affected
area.29 Primary presentation in the skin is rare.
Epithelioid schwannomas generally follow a benign clinical Histological features
course with only rare recurrences following incomplete or mar- Most cellular schwannomas are at least partially encapsulated
ginal excision.15,21 and well circumscribed. When compared to the conventional
subtype, cellular schwannomas display a higher degree of
Differential diagnosis cellularity, with spindle cells arranged in various growth pat-
Differential diagnosis of epithelioid schwannomas is broad and terns, including compact fascicular and occasionally a
includes epithelioid malignant peripheral nerve sheath tumour fibrosarcoma-like herringbone pattern, storiform or whorled
(EMPNST), metastatic carcinoma, ossifying fibromyxoid tumour pattern (Figure 7). While Antoni A-like areas predominate, focal
(OFMT), myoepithelial tumour, as well as melanocytic pro- Antoni B-like areas are frequently present. Tumour cells may be
liferations. Additional immunohistochemical stains that help cytologically bland, but nuclear hyperchromasia and up to
establish the tumour cell line of differentiation coupled with moderate pleomorphism is not unusual.30,31 Mitotic activity can
molecular genetic studies often help to resolve this diagnostic be increased, but the vast majority of cellular schwannomas
dilemma. display less than 4 regular mitotic figures per 10 HPF.29,31 The
proliferation index (MIB-1/Ki67) is mostly low (<20%) but may
show hotspot regions with higher proliferation rates.31 Foci of
Cellular schwannoma
necrosis were found in up to 11% of cases, sometimes in asso-
Introduction ciation with previous trauma.29
This variant of schwannoma is distinguished by high cellularity,
a fascicular growth pattern and mild cytological atypia. Immunohistochemical features
Apart from diffuse, strong S100 protein positivity shared among
Clinical features all schwannoma subtypes, cellular schwannomas, especially in
Cellular schwannomas most commonly affect middle aged the retroperitoneum, frequently express glial fibrillary acidic
adults, with a slight predilection for females. The vast majority of protein (GFAP) and cytokeratin AE1AE3.19 CHD4 (chromodo-
cases are sporadic, with only a handful of reports confirming main helicase DNA-binding protein 4) has shown promise in one
association with either type of neurofibromatosis and familial study to differentiate between cellular schwannomas and

Figure 7 Cellular schwannoma. (a) This variant of schwannoma is characterized by increased cellularity and a fascicular growth pattern. (b) A more
storiform growth pattern is often also present. (c) Brisk mitotic activity is not uncommon. (d) Nuclear atypia is usually mild to moderate.
MPNST, since it showed positive nuclear and cytoplasmic reac- characterized by anastomosing or intersecting cords/strands of
tion in the vast majority of cellular schwannomas, while only Schwann cells forming a microcystic or reticular growth
nuclear but not cytoplasmic positivity in the MPNSTs.32 pattern.17
Treatment and prognosis Clinical features

Cellular schwannomas follow an essentially benign clinical As with conventional schwannoma, most cases of microcystic/
course and are cured by complete surgical excision, although reticular schwannoma have been reported in adults and none of
occasional recurrences, even several years after primary resec- the cases were associated with neurofibromatosis type 1 or type 2
tion, are not unusual.30,31 Increased mitotic activity was found to or schwannomatosis.17,33 Cutaneous tumours can present as
be predictive of possible recurrence. polypoid lesions or a painless nodule.17,33
Differential diagnosis Histological features

The main differential diagnosis of cellular schwannoma is ma- Dermal and/or subcutaneous tumours are generally well cir-
lignant peripheral nerve sheath tumour.29,31 A whorling growth cumscribed, mostly encapsulated, with only occasional micro-
pattern with an absence of fascicles, the presence of some of the scopic foci of limited infiltrative growth (Figure 8).17,33 Many
conventional schwannoma features (i.e., fibrous capsule, sub- tumours are multinodular, each nodule being surrounded by a
capsular lymphocytic infiltrates and macrophages), positivity for fibrous capsule, some containing EMA positive perineurial
SOX10, neurofibromin and p16 on immunohistochemistry and cells.17,33 Tumour cells are bland, spindled, sometimes focally
generally low proliferative activity as demonstrated by Ki67, all epithelioid, with round or oval, tapered nuclei and inconspicuous
favour cellular schwannoma.31 In contrast, the presence of ne- nucleoli.17,33 Rarely, multinucleated giant cells may be present.33
crosis, perivascular hypercellularity, tumour bulging into Tumour cells are predominantly arranged in a microcystic,
vascular lumens, loss of SOX10, neurofibromin and p16 immu- reticular or lace-like meshwork with abundant basophilic myx-
noreactivity but positive EGFR expression and uniform Ki-67 of oid/mucoid, fibrillary or hyalinised/collagenous matrix.17,33
at least 20%, all favour MPNST rather than cellular Mitotic activity is sparse and does not exceed 3 regular mito-
schwannoma.31 ses/50 HPF.17,33 Prominent nuclear pleomorphism and necrosis
are not features of microcystic/reticular schwannoma.17,33
Microcystic/reticular schwannoma
Introduction All tumours show diffuse, strong S100 protein positivity and
Microcystic/reticular schwannoma is a morphologic subtype of variable GFAP positivity, while being consistently negative for
schwannoma first described by Liegl et al. in 2008.17 Excep- EMA, cytokeratins, smooth muscle actin, desmin, p63, calponin,
tionally rare in the skin, this distinctive variant of schwannoma is chromogranin and synaptophysin.17,33

Figure 8 Microcystic/reticular schwannomaa. (a) This example presented as a well-demarcated nodule in the dermis. (b) Tumour cells are typically
growing in interconnecting strands with the formation of microcystic/reticular pattern. (c) Some degrees of degenerative atypia of the lesional cells
is usually seen. (d) Tumour cells are diffusely positive for S100 protein.
Treatment and prognosis life as a solitary and occasionally painful nodule on the neck,
Microcystic/reticular schwannomas are benign tumours. Com- trunk or extremities.36,37 Association with schwannomatosis, in
plete excision is curative.17,33 one case with a germline SMARCB1 mutation, has rarely been
reported.36
The main differential diagnosis of microcystic/reticular Histological features
schwannoma includes nerve sheath myxoma, reticular peri- The tumour is characterized by well circumscribed (multi)
neurioma, myxoid cellular neurothekeoma, lipomatous neurofi- nodular proliferation in the dermis and/or subcutis.37 The
broma, myxoid variant of dermatofibrosarcoma protuberans, distinctive feature of the tumour is the formation of rosette-like
extraskeletal myxoid chondrosarcoma and myoepithelioma. structures around blood vessels or eosinophilic collagenous
Only nerve sheath myxoma and reticulated perineurioma will be cores.37 The lesional cells are small, with round to oval nuclei,
discussed briefly. Unlike microcystic/reticular schwannomas, indistinct nucleoli and scant cytoplasm.36,37 Necrosis or promi-
nerve sheath myxomas do not form lace-like or reticular struc- nent nuclear/cell pleomorphism is absent. Mitoses are either rare
tures, they show a striking predilection for distal extremities and or absent.37 Areas of conventional schwannoma can usually be
they often recur after simple local excision.5 The reticular variant identified in the majority of the cases, especially near the
of perineurioma shares a strikingly similar morphology with capsule.35
reticular schwannoma but can be distinguished by the EMA
positivity of the lesional cells.34 Immunohistochemical features
Tumour cells are consistently positive for S100 protein, variably
positive for GFAP, and negative for epithelial markers (cytoker-
Neuroblastoma-like schwannoma
atins), EMA, melan A, synaptophysin, chromogranin, CD99,
Introduction neuron-specific enolase, neurofilament, CD34 and MUC4.36,37
Goldblum et al. first described a variant of schwannoma with EMA may sometimes delineate perineurial cells in the fibrous
large, Homer Wright-like pseudorosettes in 1994.35 Less than 30 capsule.37
cases have been reported since the initial description, making
neuroblastoma-like schwannoma one of the rarest variants of Treatment and prognosis
schwannoma.36,37 Complete excision is curative. Except for one report of an
epithelioid MPNST arising in schwannoma with focal
Clinical features neuroblastoma-like features in a patient with schwannomatosis
Neuroblastoma-like schwannoma shows a female predominance and germline SMARCB1 mutation,36 all other cases followed an
(M:F¼1:4e6) and presents most commonly in the 4th decade of indolent course.

Differential diagnosis Localized tumours are grossly soft, small, pedunculated le-
Distinction from Ewing sarcoma and neuroblastoma is often sions; diffuse neurofibromas exhibit a plaque-like appearance,
straightforward since the latter two entities most commonly whereas plexiform variants usually form larger, deeper and often
appear in a different clinical setting and have a markedly disfiguring tumours, involving larger nerve trunks with a
different immunophenotype from schwannoma. Hyalinising distinctive “bag of worms” appearance.
spindle cell tumour with giant rosettes is a variant of low-grade
fibromyxoid sarcoma. However, MUC4 positivity and the pres- Histological features
ence of characteristic FUS-CREB3L2 (or less commonly, FUS- Most localized and plexiform neurofibromas are well circum-
CREB3L1) translocation can distinguish the two entities.38 scribed but unencapsulated, while the diffuse type shows dermal
based proliferation, surrounding pre-existing adnexal structures,
with ill-defined infiltration into subcutaneous tissue. Tumour
Cutaneous neurofibroma
cells are usually bland, fusiform or spindled, with wavy and
Introduction tapered nuclei (Figure 9). Multinucleated floret-like giant cells
Neurofibromas are common benign peripheral nerve sheath tu- may also be observed.42 Meissner’s corpuscle-like structures,
mours composed of an admixture of Schwann cells, perineurial formed by Schwann cells, are most commonly seen in diffuse
cells, endoneurial fibroblasts, cells with intermediate differenti- neurofibromas. Stroma is often loosely mucinous/myxoid with
ation between these cells, axons and intralesional nerve bundles/ variable collagen fibres, except in the diffuse variant, which
twigs. They exhibit various architectural and morphologic pat- usually exhibits a more uniform collagenous and fibrillary
terns, giving rise to a number of different variants, including background (Figure 10). Mitotic figures are absent (or excep-
myxoid, epithelioid, cellular, lipomatous, sclerotic/hyalinized, tionally rare, see below) and so is necrosis.
pigmented, dendritic and atypical (including atypical neuro- Myxoid neurofibromas are a variant of localized neurofi-
fibromatous neoplasm of unknown biologic potential, ANNUBP). bromas, not associated with neurofibromatosis type 1,
Nevertheless, the simplest classification into three categories is exhibiting relative hypocellularity due to prominent myx-
usually applied: localized, diffuse and plexiform variants. oid matrix containing delicate collagen fibres. They can be
distinguished from myxoid schwannomas by the presence
Clinical features of intralesional axons.
While the majority of neurofibromas are sporadic solitary tu- Epithelioid neurofibromas are also a variant of localized
mours at superficial cutaneous sites, up to 10% occur in the neurofibromas, exceedingly rare, occurring mostly in a
setting of neurofibromatosis type 1 (von Recklinghausen’s dis- sporadic setting and rarely in the background of neurofi-
ease).39 Conversely, more than 99% of patients with neurofibromatosis type 1.16 They are distinguished by a prolifer-
bromatosis 1 develop multiple neurofibromas, usually by late ation of epithelioid cells in the background of an otherwise
adolescence and often of diffuse or plexiform types.40,41 typical neurofibroma.
Figure 9 Localized neurofibroma. (a) An unencapsulated well-demarcated proliferation of spindle cells is seen in the dermis. (b) Dermal proliferation is
often distinguished from the epidermis by a so-called ‘grenz zone’ lacking lesional cells. (c) Spindle cells with oval, elongated, wavy or comma-
shaped uniform nuclei lacking atypia are typical of the entity. (d) Scattered mast cells are often present, and are more prominent in the myxoid areas.

Figure 10 Diffuse neurofibroma. (a) Low power magnification delineating a plaque-like proliferation of spindle cells in the dermis and subcutaneous
fatty tissue. (b) Bland spindle cells are seen surrounding and infiltrating lobules of subcutaneous fat. (c) The tumour is composed of elongated spindle-
shaped cells with fusiform and/or round nuclei and eosinophilic cytoplasm. (d) A collagenous stroma is present in the background.
Cellular neurofibromas show similar features to conven- and stain positive for S100 protein, Melan A, MiTF, focally
tional localized neurofibromas, with the exception of for HMB45 and tyrosinase.46
increased cellularity. Tumours with hypercellularity Dendritic cell neurofibromas are composed of two distinct
accompanied by atypia and/or mitotic activity should cell types.47 Type I cells are small, with dark nuclei
rather be classified as atypical neurofibromatous neoplasm resembling lymphocytes, while type II cells are large, with
of unknown biologic potential.43 pale vesicular nuclei and abundant eosinophilic cyto-
Lipomatous neurofibromas occur in sporadic, neurofibro- plasm, with characteristic dendritic processes highlighted
matosis type 1 and segmental neurofibromatosis set- on immunostains.47 In the majority of tumours, type I cells
tings.42,44 Most tumours are of classic (localized) type, are arranged concentrically around the larger type II cells,
although diffuse variants can also be seen. They most thus forming a pseudorosette-like structure, although oc-
commonly present as large tumours in the head and neck casionally, a zonal distribution of both cell types gives a
region of older, female patients.44 Fatty change is often more pseudogranulomatous appearance.47,48 Aside from
accompanied by vascular proliferation and multinucleated type I and type II cells, fibroblasts, axons and mast cells are
floret-like giant cells.42,44 also commonly present to a variable extent.47,48
Sclerotic/hyalinized neurofibromas are a small subset of
localized neurofibromas that show a predilection for the Immunohistochemical features
skin of breast and trunk and occur mostly in a sporadic The variegated cell population consisting of Schwann cells, fi-
setting. They exhibit prominent sclerotic stroma, with broblasts, axons, perineurial and mast cells can be highlighted
bland neoplastic spindle cells and often numerous mast immunohistochemically by S100 protein, CD34, neurofilament,
cells embedded among thick collagen bundles arranged in epithelial membrane antigen (EMA) and CD117, respectively.
fascicles and/or whorls.45 The MIB1 (Ki67) proliferation index is typically low and does not
Pigmented neurofibromas show the typical morphology of differ between primary tumours and recurrences.
a diffuse neurofibroma, with the bulk of the tumour
residing in the dermis and showing infiltration into sub- Molecular genetic features
cutaneous fat.46 Their distinctive feature is the presence of Neurofibromas in the setting of neurofibromatosis 1 develop due
melanin pigment-containing cells, usually of spindle/den- to bi-allelic inactivation of the NF1 gene in a Schwann cell, after a
dritic and sometimes epithelioid morphology, which stain germline NF1 mutation in one allele is followed by an acquired
positive for Masson Fontana but not for iron.46 The pig- somatic NF1 mutation in the other allele.49 The NF1 gene alter-
mented cells show typical melanocytic immunophenotype ations are of various types, though, including various NF1

microdeletions, pathogenic intronic mutations and several based on the presence of a variety of cell types (also demon-
intragenic point mutations.50 Although there are more than two strable by ancillary techniques) and the absence of a fibrous
thousand different pathogenic NF1 variants, only a few specific capsule in neurofibromas.
genotypes have been linked to specific neurofibromatosis 1
phenotypes.50 NF1 microdeletions and missense mutations in
Plexiform neurofibroma
codons Leu844, Cys845, Ala846, Leu847 and Gly848 have been
associated with a worse clinical presentation, including large Clinical features
tumour burden and increased risk of developing malignancy,50 While virtually all patients with neurofibromatosis 1 develop
while a specific 3-codone deletion, c.2970_2972del [p.Met992- cutaneous neurofibromas, the plexiform variant, which usually
del], results in a fairly mild NF1 phenotype without cutaneous or arises in the first two decades, occurs in 30e50% of NF1 pa-
plexiform neurofibromas.51 tients.41 Conversely, plexiform neurofibromas occur commonly,
Less is known about genetic alterations in non-syndromic but not exclusively, in the setting of NF1.54 Two distinct subtypes
neurofibromas, in which a recurrent KIR2DL5 N173D mutation, of plexiform neurofibroma are recognized, nodular and diffuse
resulting in disinhibition of Schwann cell proliferation, has been (also called elephantiasis neurofibroma), with the latter showing
demonstrated in one study.52 a predominance for the dorsal aspect of the trunk, followed by
the head and neck region, lower and upper extremities.
Non-syndromic neurofibromas are generally benign pro- Histological and immunohistochemical features
liferations. Symptomatic tumours are cured by local excision. Histologically, plexiform neurofibromas are composed of the
NF1-associated tumours, especially plexiform and sometimes same variegated cell types as the classic variants, usually with a
diffuse neurofibromas, may be much larger and debilitating, fairly prominent myxoid background, but with multiple tumour
making surgical treatment challenging or even impossible. nodules arranged in a plexiform pattern (Figure 11). Up to 10%
The lifetime risk of a NF1 patient developing MPNST is 8 of plexiform neurofibromas may contain cells with multi-
e13%, while malignant transformation to conventional or vacuolated, mucin-filled cytoplasm that show an immunophe-
epithelioid MPNST is exceptionally rare in sporadic cases of notype intermediate between fibroblasts and perineurial cells
neurofibromas, most often after multiple recurrences.53 (S100-, CD34þ, focal GLUT1þ, focal Claudin1þ).55
Differential diagnosis Treatment and prognosis

Melanocytic proliferations may be difficult to distinguish from Plexiform neurofibromas are benign neoplasms. However, of all
neurofibromas and it is important to note that expression of neurofibroma subtypes, MPNST most commonly arises in the
melanocytic markers may be encountered in neurofibromas. plexiform variant, especially in the larger, deep-seated tumours
Distinction from other benign peripheral nerve sheath tumours is of NF1 patients.54
Figure 11 Plexiform neurofibroma. (a) Unencapsulated and poorly demarcated proliferation is present in the subcutis. (b) Tumour cells diffusely
infiltrate the affected nerves. (c) Higher magnification depicting expanded nerves. (d) This area reveals hypocellular proliferation of bland tumour
cells. Note the absence of atypia and mitotic activity.

Atypical neurofibroma and atypical neurofibromatous sufficient for the development of atypical neurofibroma,
neoplasm of uncertain biologic potential (ANNUBP) whereas for the development of ANNUBP, biallelic inactivation
of CDKN2A/B has to be acquired.58 This is in accordance with
Atypical neurofibromas and atypical neurofibromatous neo-
studies in mice that showed that CDKN2A (Arf) functions as a
plasms of uncertain biologic potential (ANNUBP) are premalig-
tumour suppressor that induces senescence and therefore
nant conditions that show distinct genetic alterations and
growth arrest of aberrantly proliferating Schwann cells with
significantly lower mutation burden than MPNST.43,56
biallelic inactivation of NF1.59
Clinical characteristics
In a non-syndromic context, atypical neurofibromas are dermal Treatment and prognosis
and/or subcutaneous, non-plexiform tumours, presenting mostly Marginal resection of atypical neurofibromas, ANNUBP and low
as a painless mass on extremities or trunk. In the setting of grade MPNST is sufficient in preventing recurrence, trans-
neurofibromatosis 1, these lesions are mostly deep-seated, may formation to high grade malignancy and metastasis, even in
be painful, show rapid growth and may show fluorodeoxy- cases of positive surgical margins.57
glucose (FDG)-positron emission tomography (PET) avidity.57
Cutaneous perineurioma
Histological characteristics
Atypical neurofibromas are characterized either by nuclear aty- Introduction
pia or hypercellularity.43 For a diagnosis of ANNUBP in the Perineurioma is a benign peripheral nerve sheath tumour
context of NF1, at least two of the following criteria need to be composed of perineurial cells, originally delineated by Lazarus
met: nuclear atypia, loss of neurofibroma architecture (loss of and Trombetta in 1978 by ultrastructural studies.60 Two main
CD34þ fibroblastic network, presence of herringbone/fascicular clinicopathological variants are recognized: an intraneural and
growth pattern etc.), high cellularity and increased mitotic ac- extraneural (soft tissue) perineurioma. In addition, perineurioma
tivity (>1/50 and <3/10 HPF) (Figure 12).43 can be an integral part of various hybrid tumours (see corre-
sponding chapter). Association of perineurioma with neurofi-
Immunohistochemical and molecular genetic features bromatosis type 1 and 2 is exceptional.61
Atypical neurofibromas and ANNUBP often harbour deletions
on the short arm of chromosome 9, resulting most often in Clinical features
inactivation of CDKN2A/B (with resulting complete loss of p16 Intraneural perineurioma shows a predilection for the extrem-
expression) and SMARCA2.56 One study compared histologic ities, in particular the sciatic nerve and its branches, of children
and genetic features of different intratumoural regions and the and young adults, with an equal gender distribution. Although
results indicated that in cells with biallelic inactivation of NF1, the proliferation is usually limited to a single nerve with a
heterozygous inactivation of the CDKN2A/B locus may be characteristic fusiform expansion of the affected nerve, multiple
Figure 12 Atypical neurofibroma. (a) Low power of a diffuse proliferation of spindle cells in a patient with neurofibromatosis type 1. (b) Small groups
of atypical spindle cells with hyperchromatic nuclei are depicted in this photograph. (c) Atypical cells are characterized by enlarged hyperchromatic
nuclei. (d) Very rare mitoses can be seen on occasion.

nerves at different sites can rarely be involved. Intraneural can vary from paucicellular to densely cellular tumours.62,64 Mitotic
growth is essentially associated with different degrees of sensory activity is absent or very low.62,64 Atypical histological features,
loss and/or motor deficiency. including scattered pleomorphic tumour cells, increased mitotic
Cutaneous perineurioma presents as a solitary, slowly rate, abrupt transition to more cellular areas and infiltrative growth
growing papule or nodule in adult patients in their 5th decade of pattern, are not associated with more aggressive biological behav-
life, with a predilection for lower limbs and trunk, generally iour.64 Several morphological variants of perneurioma have been
measuring less than 1 cm in diameter.62 Interestingly, a scle- recognized: sclerosing, reticular, plexiform, with collagen rosettes,
rosing variant has a particular predilection for the fingers and epithelioid, pseudolipoblastic, lipomatous, granular cell and
palms of young adults and appears to be more common in Pacinian-like perineurioma.34,63,65
males.63
Soft tissue perineurioma has a wide site distribution with a Immunohistochemical features
predilection for limbs, followed by trunk and head and neck Perineuriomas are characterized by EMA and collagen IV posi-
area.64 Middle aged adults are most commonly affected, with no tivity, show variable positivity for claudin-1, GLUT-1, CD34, and
sex predominance.64 The soft tissue variants are generally larger smooth muscle actin64,66,67 and are negative for S100 protein,
than cutaneous tumours, with a mean size of about 4 cm.64 GFAP, neurofilament and desmin.64,66 On occasion, staining with
EMA can be absent, focal and/or faint due to antigen dilution and
Histological features can thus be overlooked.66
Intraneural perineurioma is characterized on cross sections of the
nerve by a proliferation of spindled perineurial cells distinctively Molecular genetic features
arranged in pseudo-onion bulb-like whorls surrounding one or Both intraneural and soft tissue perineuriomas have been asso-
several more centrally located Schwann cells and axons. Longi- ciated with abnormalities of chromosome 22, generally involving
tudinal sections reveal ill-defined parallel layers of perineurial the neurofibromatosis 2 gene.68 In addition, isolated cases of soft
cells surrounding the nerve fibres. tissue perineuriomas have revealed loss of chromosome 13,
Soft tissue perineurioma, including pure cutaneous variants, is a 10q24 rearrangements or complex three-way translocation
well-demarcated non-encapsulated proliferation of perineurial cells (2,9,4).69 Perineuriomas typically display simple karyotypes,
arranged in various growth patterns, including whorled, storiform, with one or few chromosomal rearrangements or numerical
fascicular, sheet-like and lamellar (Figure 13).62,64 The lesional cells changes.
typically display a spindled morphology with delicate inconspic-
uous bipolar pale eosinophilic cytoplasm and curved/wavy nuclei Treatment and prognosis
in the background of collagenous, sclerotic or myxoid stroma.62,64 Complete resection of an intraneural perineurioma with possible
Not uncommonly, areas with a more epithelioid morphology of nerve grafting results in loss of function of the affected nerve.
tumour cells can be observed and the cellularity of the proliferation The treatment approach should therefore be tailored with regard
Figure 13 Cutaneous perineurioma. (a) Low power magnification reveals a well-demarcated non-encapsulated nodular proliferation in the dermis. (b)
The tumour is composed of bland epithelioid and spindled tumour cells growing in the background of a myxoid stroma. (c) Tumour cells display a vague
storiform pattern in this area. (d) On immunohistochemistry, EMA staining can often be patchy and faint due to the dilution of the antigen.

to clinical symptoms and balanced accordingly. Complete exci- Histological features

sion of an extraneural perineurioma is curative. Different components of the hybrid tumours can be either 1) clearly
distinguished from each other, with an abrupt transition and a
Differential diagnosis characteristic biphasic growth pattern or 2) intimately inter-
The main distinction of intraneural perineurioma is with trau- mingled, also designated monophasic. In the latter group of pro-
matic neuroma and other intraneural variants of benign periph- liferations, distinction of the two, or even more components can be
eral nerve sheath tumours. notoriously difficult without additional immunohistochemistry.
Differential diagnosis of extraneural perineuriomas is broad Schwannomatous areas are distinguished by spindled
and depends upon the histological subtype of perineuroma and Schwann cells with wavy tapering nuclei, pale eosinophilic
site of occurrence. Essentially, diverse entities (benign and ma- cytoplasm and indistinct cells borders. The typical Antoni A and
lignant) need to be excluded based on a combination of histo- Antoni B areas can be absent. Degenerative nuclear atypia is
logical features, immunohistochemistry and additional molecular fairly common and is present in up to 25% of cases.71 Interest-
genetic studies, whenever needed, and include fibrous histiocy- ingly, Schwann cells in schwannomas are large spindle cells with
toma, other peripheral nerve sheath tumours, superficial acral plump nuclei, while in neurofibromas Schwann cells are
fibromyxoma, solitary fibrous tumour, dermatofibrosarcoma considerably smaller.71 Neurofibromatous areas are composed of
protuberans and low-grade fibromyxoid sarcoma (the list is by Schwann cells with wavy elongated nuclei and scant cytoplasm,
no means complete). admixed with fibroblasts and collagen, often growing in a diffuse
or plexiform pattern. Most neurofibromas contain variably
Hybrid peripheral nerve sheath tumours prominent scattered axons, while they are absent or less com-
mon in schwannomas.71 Perineuriomatous areas usually reveal a
Introduction whorled, storiform, lamellar and less often fascicular growth of
Originally reported by Feany et al. in 1998, hybrid peripheral perineurial cells, which are distinguished by spindled and less
nerve sheath tumours are defined as tumours composed of more often more rounded cells with uniform wavy nuclei and delicate
than one type of peripheral nerve sheath tumour, including elongated bipolar cytoplasmic processes (Figure 14).
schwannoma, perineurioma and neurofibroma.70 Schwannoma/
perineurioma and neurofibroma/schwannoma are the most Immunohistochemical features
common types of hybrid tumour, while neurofibroma/perineur- The schwannomatous component is diffusely positive for S100
ioma is distinctly uncommon.71 Exceptionally, hybrid tumours protein and SOX10.71 Rare axons can on occasion be demon-
consist of three different schwannomatous, perineuriomatous strated by neurofilament stain. The perineuriomatous part can be
and neurofibromatous components.72 Recently, an unusual confirmed by EMA, GLUT1 and claudin-1 positivity. In cases of
combination of perineurioma and cellular neurothekeoma has hybrid Schwannoma/perineuroma, a dual immunohistochem-
also been reported73 as well as hybrid perineurioma/granular cell istry for S100 protein and EMA characteristically reveals an
tumour.74 admixture of distinct cell populations without co-expression of
the two markers by individual cells.71 Neurofibromatous areas
Clinical features are highlighted by an admixture of cell types: Schwann cells are
As a group, hybrid peripheral nerve sheath tumours most positive for S100 protein (roughly about 50% of the cell popu-
commonly present as a solitary, well-circumscribed and unen- lation); they are admixed with CD34 positive fibroblasts and
capsulated nodule in the dermis and/or subcutis, measuring neurofilament positive axons.
from 1 to 8 cm in greatest diameter (mean size of 3 cm).70,71 The
tumour develops across a wide age range and anatomic distri- Molecular genetic features
bution, but tends to predominate in the 4th decade of life, with a A very recent study on schwannoma/perineurioma confirmed
predilection for extremities.71 They are usually asymptomatic recurrent fusion events involving the VGLL3 gene in 14 out of 18
and can on occasion be painful.71 Some studies have revealed a analysed cases (77%), with a variety of fusion partners,
female predilection for hybrid schwannoma/perineurioma. including CHD7, CHD9 and MAMLD1.77 Unrelated fusions,
Hybrid schwannoma/perineurioma generally develops in a nevertheless, including DST-BRAF and SQSTM1-CDX1 fusion
sporadic setting.71 In contrast, both hybrid neurofibroma/ genes, were detected in one case each.77 Another study on
schwannoma and hybrid neurofibroma/perineurioma can be neurofibroma/schwannoma demonstrated loss of heterozygosity
associated with tumour syndrome, including neurofibromatosis at 22q in two out of 5 analysed cases (44%), but also suggested
type I (NF1), neurofibromatosis type 2 (NF2) and schwanno- involvement of alpha-T-catenin/CTNN3 in the pathogenesis of
matosis.75 Syndromatic hybrid tumours are multiple in over neurofibroma/schwannoma.78
50% of cases.75 Furthermore, over 70% of patients with
schwannomatosis develop a single or multiple hybrid neurofi- Treatment and prognosis
broma/schwannoma.76 In addition, about 90% of NF1 patients Hybrid tumours generally follow a benign clinical course. Com-
and over 25% of NF2 patients develop a single or multiple plete excision is curative. Recurrences following marginal exci-
hybrid neurofibroma/schwannoma during the course of the sion are exceptional, as is malignant transformation of a hybrid
disease.76 Lastly, hybrid neurofibroma/perineurioma often schwannoma/perineurioma to malignant peripheral nerve
shows association with NF1.76 sheath tumour.

Figure 14 Hybrid neurofibroma/reticulated perineurioma. (a) Low power magnification delineates a well demarcated multilobular tumour. (b) Two
different growth patterns can be seen: a more diffuse (lower left) and reticulated (upper right). (c) The majority of the tumour cells within diffuse
growth pattern are positive for S100 protein. (d) EMA positivity nicely highlights perineurial cells in the reticulated areas.
Differential diagnosis patients is mandatory to confirm the possible syndromatic

Hybrid peripheral nerve sheath tumours have to be distinguished association.79,80,82
from other benign nerve sheath tumours, including schwan-
noma, neurofibroma and perineurioma, as well as malignant Clinical features
peripheral nerve sheath tumours (see corresponding chapters in Presentation of the tumour can be either sporadic or syndromatic
this review). in the context of Carney complex, an autosomal dominant con-
dition characterized by a combination of cutaneous and cardiac
Malignant melanotic schwannian tumour myxomas, spotty skin pigmentations and endocrine over-
Introduction activity.80 Malignant melanotic schwannian tumour mainly pre-
Malignant melanotic schwannian tumour is a malignant periph- sents as a single lesion.79,80 Nevertheless, about 20% of the
eral nerve sheath tumour of a putative neural crest origin with tumours have multifocal presentation, thereby increasing the
dual schwannian and melanocytic differentiation.79 The tumour probability of being associated with Carney complex.80 Although
represents less than 1% of peripheral nerve sheath tumours.80 initial publication by Carney suggested an association of malig-
Originally reported by Millar in 1932 as a malignant melanotic nant melanotic schwannian tumours with a familial syndrome to
tumour of ganglion cells arising from the thoracic sympathetic be as high as 55%,80 subsequent studies have established a
ganglion,81 the synonyms used in the literature include melanotic significantly lower association of up to 5%.79 While non-
schwannoma and/or melanocytic schwannoma. Recently, syndromatic tumours typically develop in the 4th decade of life
melanotic schwannoma has been reclassified as a malignant (mean 33.2 yrs), tumours arising in the context of Carney com-
melanotic schwannian tumour due to the lack of correlation plex generally present a full decade earlier, in young adults in
between histological features and often aggressive biological their 3rd decade of life (mean 22.5 yrs).80 Non-syndromatic and
behaviour in a substantial number of cases.79 syndromatic tumours show nearly equal gender distribution.79,80
A recent review of pure intradermal variants suggested a more Malignant melanotic schwannian tumour shows a predilec-
indolent behaviour in comparison with subcutaneous and non- tion for spinal and autonomic nerve roots, as well as the
cutaneous counterparts and an alternative name has been gastrointestinal tract.79,80,83 However, a myriad of clinical sites
offered for tumours occurring in the dermis, namely low grade have been reported, including visceral organs, brain, trachea and
melanotic schwannian tumour or atypical melanocytic schwan- bronchus, bone, genital tract, retroperitoneal space, parotid
nian tumour.82 gland, skin and soft tissues. The clinical symptoms are generally
Importantly, since malignant melanotic schwannian tumours related to the site of origin and size of the tumour, and most
can develop in the background of, or be the first manifestation of commonly include pain coupled with neurological
a Carney complex, corresponding diagnostic work up of these symptoms.79,80

Cutaneous variants of malignant melanotic schwannian tumour containing no or little pigment generally enable a more
tumour are exceptionally rare, with about 20 cases reported in detailed analysis of cell morphology. The lesional cells have
the literature.82,84 In the skin, malignant melanotic schwannian finely granular cytoplasm, the nuclei are round, oval or elon-
tumour presents as a slowly growing nodule or mass, extending gated, vesicular, often with intranuclear cytoplasmic pseudo-in-
into the subcutis.82,84 The most common site of occurrence in the clusions.80,83 Prominent vacuolisation of the cytoplasm
skin is the trunk (about 2/3 of the cases). In contrast to the non- mimicking lipoblasts can be seen in up to 60% of cases.79,80
cutaneous variants, which are commonly larger than 5 cm in Nucleoli are often small and indistinct.80,83 The nuclei are
diameter,80 cutaneous malignant melanotic schwannian tumours often characteristically grooved, resembling coffee beans. Nu-
are much smaller, with a reported size ranging from 15 to clear pleomorphism is usually mild and mitotic activity is absent
40 mm.82 or low. Nevertheless, at the other end of the morphological
spectrum of malignant melanotic schwannian tumours, tumour
Histological features cells display a marked nuclear pleomorphism, prominent
The tumours are usually well-circumscribed nodular or multi- nucleoli, increased mitotic activity, often coupled with areas of
nodular proliferations (Figure 15).79,80 An incomplete capsule tumoral necrosis.79,80,83 Psammoma bodies are present in the
can be observed in a minority of cases.79,80 Nevertheless, infil- majority of cases, and their number varies from scant to
trative growth into surrounding fibroadipose tissue is often numerous.79,80,83 A morphological variant with psammoma
present, at least focally.80 Malignant melanotic schwannian tu- bodies has also been designated a psammomatous melanotic
mours are composed of an admixture of spindled, often dendritic schwannoma,80 in contrast to a non-psammomatous variant
cells and more polygonal epithelioid cells growing in interlacing lacking this characteristic feature. Additional morphological
fascicles, sheets or nests, with occasional areas of focal whorl- features include variably abundant melanophages, intralesional
ing.79,80,83 A plexiform growth pattern has exceptionally been fat, lymphocytic infiltrates, hyalinised blood vessels, areas of
reported in the skin, and is characterized by multinodular haemorrhage and metaplastic bone formation.80 In contrast to
growth in the dermis, lack of melanin pigment and a rim of conventional schwannoma, palisading of the nuclei, Verocay
perineurial cells at the periphery of the nodules. While a gradual bodies, formation of microcystic areas and hyalinisation of blood
transition from spindled to epithelioid cells can often be vessels are distinctly uncommon.79,80
observed, a spindle cell morphology usually predominates.79,80 Unfortunately, no morphological features predict the biolog-
Melanin pigment is an integral part of the tumour, with a ical behaviour of the tumour and even proliferations lacking
striking variation in tumour cell pigmentation ranging from mitotic activity can disseminate widely, with a poor
small amounts of cytoplasmic melanin to abundant melanin outcome.79,80,83 Nevertheless, more than 2 mitoses per 10 high
pigment obscuring the cell morphology.79,80 Areas within the power fields are predictive of metastatic spread.79
Figure 15 Malignant melanotic schwannian tumour. (a) A well-demarcated tumour is seen in this example. Note areas with melanin deposition. (b)
The tumour is composed of an admixture of epithelioid and spindle cells containing variable amounts of melanin in the cytoplasm. (c) Psa-
momatous bodies can be scant. Note mild nuclear atypia and lack of mitotic activity. (d) The tumour is diffusely positive for different markers of
melanocytic differentiation. S100 protein immunohistochemistry is depicted in this photograph.

Immunohistochemical features on morphological grounds alone, the two proliferations have

Tumour cells are typically positive, often in combination, for at different genetic signatures. Pigmented epithelioid melanocytoma
least one marker of melanocytic differentiation, including S100 is distinguished genetically by mutations in the PRKAR1A gene
protein, melan A, HMB45 and tyrosinase.79 A complete lack of coupled with BRAF mutations, PRKCA fusions, MAP2K1 in-frame
staining for S100 protein can on occasion be observed, although deletions and GNAQ mutations.86 Such genetic aberrations have
other markers of melanocytic lineage are usually expressed, at not been reported in malignant melanotic schwannian tumours.
least focally.79 CD34 positivity has been reported in a limited Cellular blue naevus, atypical cellular blue naevus (melano-
number of cases. The tumours are consistently negative for cytoma) and malignant melanotic schwannian tumours at the
cytokeratins, GFAP and EMA.79 Loss of PRKAR1A expression can low grade morphological spectrum display significant histologi-
signify association with Carney complex.79 cal overlap. Nevertheless, on a genetic level, confirmation of
GNAQ or GNA11 mutations, which are distinctive of the blue
Molecular genetic features group of melanocytic proliferations, helps to distinguish them
A subset of tumours exhibit PRKAR1A genetic aberrations.82,85,86 from malignant melanotic schwannian tumours.90
While trisomy 6p and ring chromosome 11 have been demon- Morphological features favouring cutaneous malignant mela-
strated in a single case, such aberrations involving chromosomes notic schwannian tumour over melanoma include a low level of
6 and 11 have not been reported in conventional schwanno- cytological atypia, predominantly spindled morphology, vacuo-
mas.87 Monosomies of chromosomes 1, 2 and 17 have also been lated (adipocyte-like) cells and the presence of psammomatous
reported in a subset of the tumours.85 Furthermore, loss of calcification.79,84 The two entities differ significantly at the mo-
chromosomes 13q, 17, 21q, 22q11.23 and 22q13.1 has been lecular level. Confirmation of MAP kinase pathway activating
detected in a single case of plexiform melanocytic schwannoma mutations, in particular in BRAF and NRAS gene(s) therefore
occurring in the skin.88 Gene expression profiling analysis clearly points to melanoma.82
demonstrated significant differences between malignant mela-
notic schwannian tumours, conventional schwannomas and Cutaneous epithelioid malignant peripheral nerve sheath
melanomas.79 tumour
Treatment and prognosis Introduction

Complete excision of the tumour is of paramount importance, Cutaneous epithelioid malignant peripheral nerve sheath tumour
but may be difficult to achieve at non-cutaneous locations. In (E-MPNST) is a variant of MPNST occurring in the dermis and/or
cases of marginal or incomplete excision, additional radiotherapy subcutis, composed predominantly (i.e., in excess of 50%) or
can be beneficial. The role of adjuvant chemotherapy in patients exclusively of epithelioid tumour cells generally displaying
with advanced disease is not clear at present. diffuse and at least moderate degrees of nuclear atypia.91,92 E-
The most recent study on 40 patients with malignant mela- MPNSTs represent less than 5% of MPNSTs.92 In contrast to
notic schwannian tumours revealed local recurrence in 35%, conventional MPNST, E-MPNSTs have a greater tendency to
development of distant metastases in 45%, while 19% of patient arise in the superficial soft tissues, occurrence from a pre-existent
with the available follow up died of the disease.79 Not uncom- benign peripheral nerve sheath tumour is uncommon and asso-
monly, metastatic spread can occur even after 5 years and long- ciation with neurofibromatosis type 1 is exceptional.91e93
term follow-up for these patients is clearly indicated.
Dermal malignant melanotic schwannian tumours generally Clinical features
follow an indolent biological course. Out of 10 cases with Cutaneous E-MPNST shows a predilection for the lower extremities
available follow up of purely intradermal variants, one tumour and trunk, displays a slight predilection for males and most
recurred locally and none was associated with distant spread.82 commonly develops in the 5th decade of life.91e93 Infrequent
Nevertheless, two out of three subcutaneous malignant mela- occurrence in children and adolescents has also been reported.92
notic schwannian tumours reported by Kaehler et al. metasta- Presentation is non-distinctive, either as a slowly growing mass or
sized, with one patient dying due to widespread dissemination of a nodule of variable duration, which can on occasion be painful.92 In
the tumour.84 contrast to deep soft tissue counterparts, cutaneous E-MPNSTs are
generally much smaller (median size 1.6 cm vs 5 cm).93
The main differential diagnosis of malignant melanotic schwan- Histological features
nian tumours presenting in the skin is with different types of The defining histological feature of E-MPNST is epithelioid
melanocytic proliferations, including pigmented epithelioid tumour cells being the predominant cell component (i.e., in
melanocytoma (PEM), the blue group of melanocytic pro- excess of 50% of the cell population), distinguished by round to
liferations (cellular blue naevi, atypical cellular blue naevi) and oval nuclei, vesicular chromatin, variably prominent basophilic
melanoma (primary or metastatic). nucleoli and abundant eosinophilic or amphophilic cytoplasm
Pigmented epithelioid melanocytoma is characterized with well-defined cell membranes92 (Figure 16). The epithelioid
morphologically by epithelioid or epithelioid and spindled mela- cells typically display diffuse and at least moderate degree of
nocytes with vesicular nuclei, prominent nucleoli and heavily nuclear pleomorphism.91 Mitotic activity is usually easily iden-
pigmented cytoplasm admixed with numerous melanophages.89 tifiable (mean 7 per 10 high power fields), and the presence of
While distinction between pigmented epithelioid melanocytoma atypical mitoses is not uncommon (Figure 17).92 The number of
and malignant melanotic schwannian tumour can be challenging mitoses appears to reflect the degree of nuclear/cytological

atypia.92 The epithelioid tumour cells are often arranged in cords, a well-circumscribed encapsulated tumour lacking significant
sheets, nodules/multiple lobules or more individual cells in the cytological atypia.91 Melanoma and E-MPNST show consider-
background of a variably abundant myxoid to collagenous able morphological overlap. Nevertheless, on immunohisto-
stroma.91e93 Necrosis is often present.91 A focal spindle cell chemistry, melanoma with an epithelioid morphology is
morphology of tumour cells is present in about one third of tu- typically positive for second line melanocytic markers, such as
mours.91 Pure cutaneous E-MPNST tends to grow as an indi- HMB45, tyrosinase and MITF.93 In addition, BRAFV600E or
vidual nodule in the dermis and/or subcutis.93 NRASQ61 positivity on immunohistochemistry generally con-
firms melanoma. In contrast, INI1/SMARCB1 loss has not been
Immunohistochemical features reported in melanoma.36,91,92,94 Myoepithelial tumours can be
Staining for S100 protein and SOX10 is usually diffuse and distinguished from E-MPNST by consistent cytokeratin posi-
strong.91e93 Focal positivity for melan A and HMB45 has tivity in the former.96 In addition, up to 40% of myoepithelial
exceptionally been reported.92 Up to two thirds of tumours tumours harbour an EWSR1 rearrangement,96 a feature not
display loss of INI1/SMARCB1, up to 60% reveal GFAP positivity present in E-MPNST.
and EMA positivity can be detected in about 15% of
cases.36,91,92,94 The tumours are negative for various cytoker- Cutaneous conventional malignant peripheral nerve
atins, desmin and CD31.91 There is no loss of H3K27me3.95 sheath tumour
Molecular genetic features Introduction
No distinctive molecular genetic changes have been reported in Cutaneous conventional malignant peripheral nerve sheath
cutaneous E-MPNST. tumour (CO-MPNST) is a malignant peripheral nerve sheath
tumour with a Schwannian or perineuriomatous line of differ-
Treatment and prognosis entiation, predominantly localized in the dermis and/or subcu-
Complete surgical excision is the treatment of choice and can be taneous fatty tissue. Although exceptionally rare in the skin,
supplemented with additional local radiotherapy and systemic cutaneous CO-MPNST typically arises in association with a pre-
chemotherapy. Although earlier studies on cutaneous E-MPNST existent neurofibroma or from small cutaneous nerves,97 ac-
suggested a more favourable biological behaviour in comparison counting for about 2% of MPNSTs.98
to deep soft tissue counterparts,93 cutaneous E-MPNST can
follow an aggressive clinical course. Clinical features
While sporadic cases of cutaneous CO-MPNST do not show any age
Differential diagnosis predominance, tumours developing in the background of neurofi-
The main differential diagnosis includes epithelioid schwan- bromatosis type 1 typically occur in younger patients.97 Interest-
noma, melanoma (metastatic or primary dermal/subcutaneous) ingly, cutaneous CO-MPNST is less often associated with NF1 in
and myoepithelial tumours. Epithelioid schwannoma is usually comparison with their deep soft tissue counterparts. While about
Figure 16 Cutaneous epithelioid malignant peripheral nerve sheath tumour. (a) Low power magnification of a nodular and infiltrative tumour in the
dermis and subcutis. (b) The tumour is composed of epithelioid cells growing in a myxoid stroma. (c) Severe cytological atypia is present in this area.

Figure 17 Cutaneous epithelioid malignant peripheral nerve sheath tumour. (a) Severe cytological atypia is often coupled with brisk mitotic activity.
Tumour cells are strongly and diffusely positive for SOX10 (b) and S100 protein on immunohistochemistry (c) (d) While tumour cell lack EMA
positivity, this antibody can highlight the presence of perineurial cells (arrows) of the pre-existing nerve.
50% of deep soft tissue MPNSTs are associated with NF1, from 23% Histological features
to 37% of cutaneous CO-MPNST develop in patients with NF1.97,99 Low power magnification typically reveals a spindle cell prolif-
They are characterized by a relatively long period of slow growth eration in the dermis and/or subcutis, with characteristic alter-
followed by a sudden acceleration of growth.97,99 Cutaneous CO- nating hypo- and hypercellular areas, with perivascular
MPNST shows a predilection for the head and neck area, with a accentuation imparting a so-called marbled growth pattern
particular preference for the scalp, followed by extremities.97 (Figure 18).100 The proliferation is usually poorly circumscribed,
Figure 18 Cutaneous conventional malignant peripheral nerve sheath tumour. (a) A large spindle cell tumour is seen replacing the entire dermis
and subcutis. (b) A storiform and more fascicular growth pattern can be noted in this photo. (c) Tumour cells display moderate nuclear atypia and
brisk mitotic activity. (d) The immunohistochemistry for S100 protein is often focal and weak.

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An Update On Cutaneous Tumours With Neural Differentiation

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MINI-SYMPOSIUM: CUTANEOUS SOFT TISSUE TUMOURS

An update on cutaneous Histological features

tumours with neural perplastic enlarged peripheral nerves composed of axons,

differentiation ensheathed by mature stratified squamous epithelium replacing

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Treatment and prognosis Cutaneous schwannoma

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Clinical features Immunohistochemical and molecular genetic features

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Treatment and prognosis Clinical features

Differential diagnosis Histological features

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Differential diagnosis Treatment and prognosis

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to clinical symptoms and balanced accordingly. Complete exci- Histological features

DIAGNOSTIC HISTOPATHOLOGY 28:1 28 Ó 2021 Published by Elsevier Ltd.

Differential diagnosis patients is mandatory to confirm the possible syndromatic

DIAGNOSTIC HISTOPATHOLOGY 28:1 29 Ó 2021 Published by Elsevier Ltd.

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Immunohistochemical features on morphological grounds alone, the two proliferations have

Treatment and prognosis Introduction

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DIAGNOSTIC HISTOPATHOLOGY 28:1 37 Ó 2021 Published by Elsevier Ltd.

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