23 Chapter 127 :: Neoplasias and Hyperplasias of

Muscular and Neural Origin

:: Lucile E. White, Ross M. Levy, &
Murad Alam
TUMORS OF SMOOTH MUSCLE early adulthood, these patients present with increas-
ing numbers of tumors, developing as many as 100
1,000 lesions. Transmission appears to be autosomal
The dermis contains smooth muscle fibers in the arrec-
dominant with variable penetrance.2 Women with
tor pili muscles, in the walls of dermal blood vessels,
multiple piloleiomyomas may also develop uterine
and in the dartos muscle of the scrotum, vulva, nipple,
leiomyomas, an entity termed multiple cutaneous and
Section 23 ::

and areola. There are three types of cutaneous smooth

uterine leiomyomatosis (also known as familial leiomyo-
muscle lesions: (1) leiomyomas, (2) leiomyosarcomas,
matosis cutis et uteri or Reed syndrome).2 In addition,
and (3) hamartomas. Smooth muscle is recognized
some families with multiple cutaneous and uterine
histologically by spindle cell shape, eosinophilic,
leiomyomatosis have been shown to cluster renal cell
fibrillary cytoplasm, and blunt-ended, oval, cigar-
cancer, and this has been termed hereditary leiomyoma-
shaped nuclei. On immunohistochemical staining,
tosis and renal cell cancer. Recently, a loss of function
Tumors and Hyperplasias of the Dermis and Subcutaneous Fat

cells express smooth muscle actin and the muscle-spe-

cific intermediate filament desmin, but are negative for
S100 protein and epithelial membrane antigen (EMA).
LEIOMYOMA
mutation in the gene encoding fumarate hydratase on
chromosome 1q42.343 has been shown to predispose
individuals to these conditions. Fumarate hydratase
catalyses the conversion of fumarate to malate in
the Krebs cycle but is also considered to be a tumor-
suppressor gene.3,4

LEIOMYOMA AT A GLANCE CLINICAL FINDINGS. The most common presen-

Benign cutaneous neoplasm derived from
arrector pili muscle (piloleiomyoma),
mammillary, dartoic or labial/vulvar muscle
(genital leiomyoma), or the walls of blood
vessels (angioleiomyoma).
Present as solitary or multiple flesh-
colored, occasionally painful papules; rarely
associated with uterine leiomyomas and
renal cell cancer.
tation is that of multiple piloleiomyomas.5 Individual
lesions range in size from several millimeters to 1 cm
and are usually reddish-brown firm papulonodules
that are fixed to the skin but freely moveable over
underling deeper structures (Fig. 127-1). They can
coalesce to form plaques or linear, grouped, or derma-
tomal patterns.5 The extensor extremities, trunk, and
sides of the face and neck are the most common loca-
tions. Patients with piloleiomyomas often have pain

Treatment: surgical; recurrence is common.

EPIDEMIOLOGY. The exact incidence of leiomyo-

mas is unknown. In one study, the 10-year incidence
was 0.04% with the majority of lesions occurring in
women.1 Although leiomyomas are thought to be rela-
tively uncommon neoplasms, the actual incidence may
be higher than previously believed due to failure to
recognize and biopsy the lesion.

ETIOLOGY AND PATHOGENESIS. Cutane-

ous leiomyomas are divided into three subsets: (1)
solitary or multiple piloleiomyomas originating from
the arrector pili muscles; (2) genital leiomyomas
originating from the mammillary, dartoic, or labial/
vulvar muscles; and (3) angioleiomyomas, originat-
ing from vascular smooth muscle. Most leiomyomas
are acquired; however, familial inheritance patterns
have been described. Especially noteworthy are Figure 127-1 Clinical photograph showing multiple leio-
1470 patients with multiple piloleiomyomas. Starting in myomas involving the back.
that may be spontaneous or secondary to cold, pres-
sure, or emotion.2,57 Possible explanations for this phe-
nomenon include pressure of the tumor on local nerve
fibers and contraction of the smooth muscle fibers.5
Genital leiomyomas are clinically similar to piloleio-
myomas except that they are usually asymptomatic.5
They commonly present as solitary, deep papulonod-
ules or occasionally, pedunculated papules on the scro-
tum, vulva, penis, or areolar region. Angioleiomyomas
present most commonly as solitary, painful subcutane-
ous nodules on the legs in women that can grow to
several centimeters in diameter.8
HISTOPATHOLOGY. Pilar leiomyomas are com-
posed of a poorly circumscribed proliferation of hap-
hazardly arranged, bland-appearing smooth muscle
cells with characteristic eosinophilic cytoplasm, blunt-
ended nuclei, and perinuclear halos in cross section.
They are located in the dermis and can infiltrate the
surrounding tissue with extension into the subcutis.
Genital leiomyomas usually resemble pilar leiomyo-
mas. Angioleiomyomas are well-circumscribed, richly
vascularized dermal or subcutaneous nodules com-
posed of well-differentiated smooth muscle fibers (Fig.
127-2). Occasionally, the vessel of origin can be identi-
fied. Leiomyomas stain positive with smooth-muscle
actin and desmin.
DIFFERENTIAL DIAGNOSIS. Differential diag-
nosis of leiomyoma includes any flesh-colored or
reddish-brown superficial or deep-seated papule or
nodule: angiolipoma, glomus tumor, eccrine spirad-
enoma, neurofibroma, nevus, or lipoma.
Figure 127-2 Histologic appearance of an angioleiomy-
oma. Compared with the pilar leiomyoma, this tumor is
more sharply circumscribed (but not encapsulated). Fur-
thermore, the smooth muscle fibers form a solid nodule
with little, if any, intervening collagen. (Hematoxylin and
eosin, 40.)
PROGNOSIS AND CLINICAL COURSE. Cuta-
23
neous leiomyomas do not regress spontaneously, and
there does not appear to be risk of malignant degen-
eration into leiomyosarcoma. A minority of patients
may also develop uterine leiomyomas and, in some
families, association with renal cell carcinoma has been
described. Occasionally, leiomyomas are associated
with polycythemia. This may be due to erythropoietin-
like activity of leiomyomas, which has been demon-
strated in tumor extracts.9
TREATMENT. Excision is the treatment of choice for
leiomyomas that cause pain or cosmetic concern; how-
ever, recurrence is common. In patients with numerous
Chapter 127
lesions, this method is impractical. Carbon dioxide laser
ablation was reported as an effective modality10 whereas
cryotherapy and electrosurgery have been used with
disappointing results.11 Pain may be a significant source
of morbidity and, when surgical intervention is not pos-
sible, potential treatment options include nitroglycerin,
::
phenoxybenzamine, nifedipine, gabapentin, intrale-
sional botulinum toxin, or topical analgesics.2,1215
Neoplasias and Hyperplasias of Muscular and Neural Origin
LEIOMYOSARCOMA
LEIOMYOSARCOMA AT A GLANCE
Rare malignant tumor of smooth muscle:
cutaneous and subcutaneous types based on
location of origin.
Presentation: enlarging cutaneous or
subcutaneous tumor most commonly on
hair-bearing areas of the lower extremities.
Recurrence rate: high, with significant
risk of metastases in case of subcutaneous
leiomyosarcoma.
EPIDEMIOLOGY. Exact incidence is unknown, but
older studies suggest that leiomyosarcomas comprise
approximately 3% of soft-tissue sarcomas.16 Superficial
leiomyosarcoma occurs in all age groups, and there
appears to be no gender predilection.
ETIOLOGY AND PATHOGENESIS. Leiomyo-
sarcoma is a rare, malignant mesenchymal tumor of
smooth muscle origin usually found in the uterus, the
retroperitoneum, gastrointestinal tract, or deep soft tis-
sue. The term superficial leiomyosarcomas refers to those
tumors whose primary site of origin is the skin. Those
derived from arrector pili or genital smooth mus-
cles are termed cutaneous leiomyosarcomas, and those
derived from blood vessel smooth muscle are termed
subcutaneous leiomyosarcomas. In some cases, tumors
have arisen in sites of earlier radiotherapy or trauma.5
Leiomyosarcomas typically arise de novo rather than
from preexisting leiomyomas. 1471
23 CLINICAL FINDINGS. Leiomyosarcomas present as
solitary, enlarging lesions most commonly on the hair-
bearing areas of lower extremities.17 They can exhibit a
variety of colors and may be painful, pruritic, or par-
esthetic. Cutaneous leiomyosarcoma usually presents
as small (<2 cm), sometimes ulcerated nodules that are
fixed to the epidermis. Subcutaneous leiomyosarcomas
tend to be larger and are usually not associated with epi-
dermal change. Some patients have multiple grouped
lesions; in one series, four of seven such patients had
a previous retroperitoneal leiomyosarcoma,18 highlight-
ing the importance of ruling out metastases in patients
with numerous superficial leiomyosarcomas.
HISTOPATHOLOGY. Leiomyosarcomas are large
Section 23 ::
tumors consisting of smooth muscle fibers arranged in
irregular, intersecting bundles and fascicles in the der-
mis and subcutis, often with infiltrating borders. Tumor
cells exhibit smooth muscle differentiation with atypi-
cal cytologic features such as nuclear hyperchromasia,
prominent nucleoli, mitosis, and necrosis (Fig. 127-3).
Tumors and Hyperplasias of the Dermis and Subcutaneous Fat
In less well-differentiated areas, highly pleomorphic
and multinucleated cells may be found.5 Granular cell,
epithelioid cell, myxoid, and sclerosing (or desmoplas-
tic) variants have been described.19 Leiomyosarcomas
must be histopathologically distinguished from other
malignant cutaneous spindle cell tumors, such as
spindle cell melanoma, spindle cell squamous cell car-
cinoma, or atypical fibroxanthoma. Leiomyosarcomas
stain positive with smooth-muscle actin, desmin, and
vimentin and occasionally with S100 and cytokeratin,
which makes distinguishing them from melanoma and
squamous cell carcinoma difficult in certain cases.5,20,21
DIFFERENTIAL DIAGNOSIS. Differential diagno-
sis of leiomyosarcoma includes any solitary, enlarging
dermal or subcutaneous nodule: lipoma, dermatofi-
broma, dermatofibrosarcoma, neurofibroma, spindle
cell melanoma, spindle cell squamous cell carcinoma,
and atypical fibroxanthoma.
Figure 127-3 Histologic examination of a leiomyosar-
coma. This tumor exhibits smooth muscle differentiation
with atypical cytologic features such as nuclear hyperchro-
masia, prominent nucleoli, and mitoses. (Hematoxylin and
1472 eosin, 400.)
PROGNOSIS AND CLINICAL COURSE. The
most important prognostic factor depends on whether
the leiomyosarcoma is of cutaneous or subcutaneous
origin. Although both cutaneous and subcutaneous
lesions may recur locally in up to one-third to one-half
of cases, the risk of metastasis is 5%10% for cutaneous
leiomyosarcomas compared with 30%60% for sub-
cutaneous leiomyosarcomas.5,9,16,17,2225 The lung is the
most common location of metastasis.
TREATMENT. Therapy for superficial leiomyosar-
coma is wide local excision with 3- to 5-cm margins and
re-excision for recurrent lesions.17 On acral locations,
complete excision may require amputation.17 Patients
with subcutaneous leiomyosarcomas should undergo
a chest X-ray for metastases. Adjuvant radiation and/
or chemotherapy have unclear benefit. Alternative
local treatment modalities in selected patients include
Mohs micrographic surgery, cryosurgery, and isolated
limb perfusion with chemotherapeutic agents.17,26
SMOOTH MUSCLE HAMARTOMA
SMOOTH MUSCLE HAMARTOMA
AT A GLANCE
Benign hamartomatous proliferation of
smooth muscle.
Presenting as a solitary patch or plaque on
the trunk.
Associated with variable pigmentation,
hypertrichosis, and follicular prominence.
Clinical and histologic features similar to
Beckers nevus.
EPIDEMIOLOGY. First described by Stokes in
1923,27 smooth muscle hamartoma has become increas-
ingly recognized during the last two decades. Most
cases are congenital but some are acquired,28,29 and
prevalence estimates of up to 0.2% in children have
been reported.29
ETIOLOGY AND PATHOGENESIS. Smooth
muscle hamartoma is a benign proliferation of mature
smooth muscle. The cause is unknown, and the major-
ity of cases are present from birth.
CLINICAL FINDINGS. Smooth muscle hamartoma
is usually found on the trunk or extremity (Fig. 127-4)
and may take one of several forms: a single patch or
plaque with or without follicular prominence, grouped
solitary lesions (rarely with a linear distribution), and
diffuse skin involvement as seen in the Michelin tire
baby syndrome.30,31 Lesions can exhibit variable hyper-
pigmentation and hypertrichosis. Vellus hairs may be
prominent. Some can produce worm-like movements

Figure 127-4 Smooth muscle hamartoma. This tumor
presented with a focal area of hypertrichosis on the leg.
(Photo from the collection of Dr. Amy Paller, MD, Childrens
Memorial Hospital, Chicago, IL.)
(vermiculation), and stroking may induce transient
induration with piloerection (pseudo-Darier sign).
Smooth muscle hamartoma shares some clinical and
histologic features with Beckers nevus. Some authors
consider these lesions a spectrum,29 whereas others
prefer to keep them separate.28,32
HISTOPATHOLOGY. There is a marked increase
of sharply circumscribed bundles of smooth muscle
fibers that are haphazardly arranged in the reticular
dermis. These fibers are sometimes associated with fol-
licular units. There may be basal layer hyperpigmenta-
tion, as well as acanthosis and papillomatosis of the
overlying epidermis. Factors that help to distinguish
smooth muscle hamartomas from pilar leiomyomas
include the grouping of smooth muscle fibers into dis-
crete bundles and the lack of intermingling of these
bundles with dermal collagen fibers.
DIFFERENTIAL DIAGNOSIS. Differential diagno-
sis of hamartoma includes congenital nevus, Beckers
nevus, caf-au-lait macule, leiomyoma, neurofibroma,
and solitary mastocytoma.
PROGNOSIS AND CLINICAL COURSE. Malig-
nant degeneration has not been reported. Although the
localized form is usually not associated with other con-
genital anomalies,29 patients with the generalized form
have been reported to have multiple associated congeni-
tal malformations33 and psychomotor retardation.33,34
TREATMENT. No specific treatment is indicated.
Surgical excision can be performed if the lesions are of
cosmetic concern.
TUMORS OF STRIATED MUSCLE
23
Tumors of striated muscle include true neoplasms of
striated muscle differentiation (rhabdomyomas and
rhabdomyosarcomas) as well as non-neoplastic neuro-
muscular and rhabdomyomatous mesenchymal ham-
artomas (RMHs).
RHABDOMYOMA
RHABDOMYOMA AT A GLANCE
Benign neoplasms of striated muscle.
Chapter 127
Most common on the head and neck of
young males.
Noncardiac rhabdomyomas usually
asymptomatic.
::
Neoplasias and Hyperplasias of Muscular and Neural Origin
Surgical excision is treatment of choice.
EPIDEMIOLOGY. Extracardiac rhabdomyomas are
extremely rare and comprise fewer than 2% of striated
muscle neoplasms.35 The adult and fetal types of rhabdo-
myomas occur predominantly in male patients. Cardiac
rhabdomyomas occur in approximately 30%50% of
patients with tuberous sclerosis (TS; see Chapter 140).36
ETIOLOGY AND PATHOGENESIS. Rhabdomyo-
mas are benign tumors of striated muscle. Extracardiac
rhabdomyomas are not associated with TS, whereas
significant portion of patients with cardiac rhabdomy-
omas are ultimately diagnosed with TS.
CLINICAL FINDINGS. Extracardiac rhabdomyo-
mas are subdivided into three types: (1) adult, (2) fetal,
and (3) genital.35,37 The designation as adult or fetal
refers to the tumors resemblance to adult or fetal skel-
etal muscle, not to the age of the patient.37 Adult and
fetal types usually arise in the soft tissues or mucosal
surfaces of the head and neck region soon after birth.
They are usually asymptomatic. The fetal type has been
repeatedly associated with basal cell nevus syndrome.37
Genital rhabdomyomas usually occur as small polyp-
oid vaginal or vulvar lesions in middle-aged women.37
HISTOPATHOLOGY. Rhabdomyomas are com-
posed of fascicles of oval and polygonal-shaped cells
with eosinophilic, often vacuolar cytoplasm and eccen-
trically placed nuclei.35 Atypia, mitosis, and pleomor-
phism are absent.
DIFFERENTIAL DIAGNOSIS. Differential diag-
nosis of rhabdomyomas includes granular cell tumor
(GCT), hibernoma, and reticulohistiocytoma.
PROGNOSIS AND CLINICAL COURSE. Extra-
cardiac and cardiac rhabdomyomas have a very low 1473
23 risk of malignant degeneration. Many cardiac rhabdo-
myomas regress spontaneously with age.
TREATMENT. The treatment of choice for symptom-
atic extracardiac rhabdomyomas is surgical excision.
RHABDOMYOSARCOMA
RHABDOMYOSARCOMA
AT A GLANCE
Malignant neoplasm of striated muscle.
Section 23 ::
Most common soft-tissue sarcoma in
children.
Presentation: subcutaneous or ulcerated
tumor on extremities or head and neck; rare
cause of blueberry muffin baby.
Tumors and Hyperplasias of the Dermis and Subcutaneous Fat
Treatment: surgical excision, chemotherapy,
and/or radiotherapy.
Prognosis: poor.
EPIDEMIOLOGY. Rhabdomyosarcoma is the most
frequent soft-tissue sarcoma of childhood with annual
incidence of 4.3/million, accounting for approximately
50% of soft-tissue sarcomas in children younger than age
15 years and 5%8% of all childhood cancers.3840 Only
approximately 0.7% occur as primary skin lesions.40
Males are more commonly affected than females.38
ETIOLOGY AND PATHOGENESIS. Rhabdomyo-
sarcomas are malignant neoplasms derived from skel-
etal muscle precursors. Primary cutaneous disease is
rare, and skin involvement is more commonly a result
of either direct extension from underlying soft tissues or
metastases.41 Four subtypes have been described based
on histologic appearance: (1) embryonal, (2) alveolar,
(3) botryoid, and (4) pleomorphic. The embryonal type
is most common, followed by alveolar. Alveolar rhab-
domyosarcoma is characterized at the molecular level
by novel fusion genes combining the forkhead (FKHR)
gene with either the PAX3 or the PAX7 gene, produc-
ing a t(2;13)(q35;q14) or t(1;13)(p36;q14), respectively.38
CLINICAL FINDINGS. Cutaneous rhabdomyosar-
coma typically presents as an enlarging subcutaneous
or ulcerated tumor involving the head and neck, the
genitourinary tract, or the extremities. A deep soft-
tissue rhabdomyosarcoma can also extend into the
overlying skin and present as a cutaneous nodule.40 In
neonates, congenital alveolar rhabdomyosarcoma is a
very rare cause of blueberry muffin baby in which
multiple cutaneous and subcutaneous metastases
present as scattered blue nodules.
HISTOPATHOLOGY. Rhabdomyosarcoma is com-
1474 posed of sheets of pleomorphic, small blue cells infil-
trating the dermis and subcutaneous tissue. High
mitotic index is present, and focal areas of necrosis
can often be identified.41 The embryonic type is com-
posed of interlocking bands of spindle cells and sheets
of small round cells whereas the alveolar type exhibits
loss of cellular cohesion leading to spaces resembling
alveoli. Immunohistochemistry can be helpful in dif-
ferentiating rhabdomyosarcoma from other small
blue cell tumors. Rhabdomyosarcomas express posi-
tivity for muscle-specific actin, desmin, myoD1, and
myogenin. Reverse transcription polymerase chain
reaction and fluorescence in situ hybridization analy-
sis can used to detect the t(2;13)(q35;q14) and t(1;13)
(p36;q14) chromosomal translocations.38,41
DIFFERENTIAL DIAGNOSIS. Differential diag-
nosis of rhabdomyosarcoma includes hemangioma,
hematoma, neuroblastoma, and other soft-tissue sar-
comas.
PROGNOSIS AND CLINICAL COURSE. Prog-
nosis is poor, with many patients succumbing to their
disease. Even with appropriate treatment, rhabdomyo-
sarcomas can recur and metastasize to regional lymph
nodes, lung, bone, and heart. Congenital alveolar rhab-
domyosarcoma has an especially poor prognosis; there
are no reports in the literature of survivors.38
TREATMENT. Treatment of rhabdomyosarcoma con-
sists of a combination of surgical excision, chemother-
apy, and radiotherapy.
BENIGN PROLIFERATIONS OF
NERVES: NEUROMAS
NEUROMAS AT A GLANCE
Nonneoplastic overgrowths of nerves;
benign.
Consist of both Schwann cells and axons.
Presentation: flesh-colored papules or
nodules.
Treatment: excision.
TRAUMATIC (AMPUTATION)
NEUROMA
EPIDEMIOLOGY. The exact incidence of traumatic
neuromas is not known. Several small studies suggest
that up to 30% of amputations result in neuromas.44,45
ETIOLOGY AND PATHOGENESIS. When a
nerve is partially or completely severed, axons and
Schwann cells can proliferate from the proximal stump
and form a disorganized tangle of nerves and fibro-
blasts, called a traumatic neuroma. Within the bundle
of nerves and fibroblasts, the axons can begin to syn-
apse and send pain signals. These signals occur spon-
taneously or after mechanical thresholds lower than
in normal nerves. The nerve proliferation typical of
accessory digits may also represent an example of
traumatic neuroma.
CLINICAL FINDINGS. Traumatic neuromas are
flesh-colored papules or nodules occurring at the sites
of previous trauma or surgery. They often occur within
suture lines and can be very painful.
HISTOPATHOLOGY. Histologically, a neuroma
appears as a collection of nerve fascicles that are
PALISADED ENCAPSULATED
23
NEUROMA
EPIDEMIOLOGY. Palisaded encapsulated neuro-
mas (PENs) present in adults, mostly in their third
to fifth decade. There appears to be no gender predi-
lection. PENs make up approximately one-fourth of
benign cutaneous neural lesions.47
ETIOLOGY AND PATHOGENESIS. PENs consist
of a hamartomatous overgrowth of Schwann cells.48
The etiology is unknown.
CLINICAL FINDINGS. PENs often present as

Chapter 127
haphazardly arranged. A fibrous or collagen sheath
asymptomatic, flesh-colored papules or nodules that
may surround neuromas, but these neuromas are not
are smaller than 1 cm in diameter. PENs are located
encapsulated by perineurium. The neuromas stain
on the face in approximately 80% of cases.47 PEN is
for EMA. Staining of the neural lesions is reviewed in
almost never diagnosed clinically; the most common
Table 127-1.
misdiagnoses are dermal melanocytic nevus, basal cell
carcinoma, and adnexal tumor.

::
DIFFERENTIAL DIAGNOSIS. Differential diag-

Neoplasias and Hyperplasias of Muscular and Neural Origin

nosis of neuromas includes hypertrophic scar, derma-
tofibroma, digital fibrokeratoma, and verruca vulgaris.
TREATMENT. Temporary pain relief can be achieved
with a local anesthetic nerve block. For more perma-
nent pain relief, surgical treatment aims either at isolat-
ing the nerve from injury or excising the neuroma.46
HISTOPATHOLOGY. PENs are well-demarcated
dermal nodules composed of fascicles of Schwann
cells (Fig. 127-5). Contrary to what the name implies,
the capsule is rarely complete and the palisading typi-
cal of schwannomas is often indistinct. Special stains
demonstrate variable numbers of axons within the
lesion. The capsule often stains with EMA, suggesting

TABLE 127-1
Staining of Neural Hyperplasias and Neoplasms

Epithelial Membrane
Neural Proliferation S100 Neurofilament Antigen (EMA) Other
Traumatic neuroma + + + Neuron-specific enolase
positive
Palisaded encapsulated + + + for the capsule
neuroma
Schwannoma + + for the capsule only Vimentin positive
Neurofibroma + Variable
Plexiform neurofibroma + +
Neurothekeoma +/ Variable Vimentin variable; usually
EMA negative
Cellular neurothekeoma CD57 positive; Ki-Mip positive
Perineurioma + Vimentin positive; neuron-
specific enolase negative
Malignant peripheral + + Variable Vimentin variable; cytokeratin
nerve sheath tumor negative; neuron-specific
enolase positive
Primitive neuroectodermal + if Neuron-specific enolase
tumor differentiated positive; CD99 positive
Granular cell tumor + Neuron-specific enolase
positive

+ = positive; = negative. 1475

23
Figure 127-5 Histologic appearance of a typical palisaded
Section 23 ::
encapsulated neuroma. The tumor is composed of fas-
cicles of Schwann cells and surrounded by a delicate cap-
sule best seen on the left. There is a suggestion of nuclear
palisading, but this is not as pronounced as that seen in a
schwannoma. (The axons that are normally also present
cannot be seen on this stain; hematoxylin and eosin, 40.)
Tumors and Hyperplasias of the Dermis and Subcutaneous Fat
a perineural origin, and the tumor body stains for S100,
suggesting a Schwann cell origin (see Table 127-1).49,50
Some PENs may actually be small dermal schwanno-
mas that contain a few residual entrapped axons.51
DIFFERENTIAL DIAGNOSIS. Differential diag-
nosis of PEN includes dermal melanocytic nevus, basal
cell carcinoma, adnexal tumor, and neurofibroma.
TREATMENT. Excision is the treatment of choice.
There is no evidence of an association between PEN
and neurofibromatosis (NF; see Chapter 141) or mul-
tiple endocrine neoplasia syndrome type 2B (MEN2B;
see Section Mucosal Neuromas and Multiple Endo-
crine Neoplasia Syndrome Type 2B).
MUCOSAL NEUROMAS AND MULTIPLE
ENDOCRINE NEOPLASIA SYNDROME
TYPE 2B
EPIDEMIOLOGY. Due to inconsistent nomenclature,
the incidence of mucosal neuromas is not known.52
ETIOLOGY AND PATHOGENESIS. MEN2B is
an autosomal dominant condition. MEN2B is caused
by germ-line mutations of the RET proto-oncogene
located on chromosome 10q11.2.53 The mutation is a
result of substituting a threonine for a methionine in
the tyrosine kinase domain of the RET protein.51
CLINICAL FINDINGS. MEN2A is characterized by
the triad of medullary carcinoma of the thyroid gland,
pheochromocytoma, and parathyroid hyperplasia. The
neoplastic spectrum of MEN2B is similar, but in addi-
tion, these patients have malformations (Marfanoid
habitus, facial dysmorphism) and overgrowth of
mucosal nerves leading to the mucosal neuromas.54,55
The neuromas appear by 2 years of age and thus
serve as an important clinical marker for identifying
1476 affected individuals in MEN2B families.53 The neuro-
mas involve all mucosal surfaces (oral mucosa, lips,
tongue, and conjunctivae) and appear as pink, pedun-
culated papules or nodules. The lips become enlarged
and bulging, and the eyelids may be everted. Other
cutaneous lesions include caf-au-lait spots, facial len-
tigines, and hyperpigmentation of the hands and feet.
HISTOPATHOLOGY. Histologically, there is hyper-
trophy of the mucosal nerves; some lesions may
resemble PENs.
DIFFERENTIAL DIAGNOSIS. Differential diag-
nosis of mucosal neuromas and MEN2B includes PEN
and mucocele.
TREATMENT. The main threat to these patients
is the development of related cancers. Virtually all
patients have a medullary carcinoma of the thyroid by
early adulthood, and approximately one-half develop
pheochromocytomas. The thyroid carcinoma is highly
aggressive. Early detection and prophylactic thyroid-
ectomy by 5 years of age are essential.53
BENIGN NERVE SHEATH
NEOPLASMS
BENIGN NERVE SHEATH NEOPLASMS
AT A GLANCE
Schwann cells and the endo- and perineurial
fibroblasts make up the nerve sheath.
Schwannomas: benign encapsulated tumors
originating from the Schwann cells.
Neurofibromas: benign nerve sheath tumors that
are proliferations of all the nerves elements.
Presentation: usually isolated lesions,
but multiple neurofibromas found in
neurofibromatosis type 1 and bilateral vestibular
schwannomas found in neurofibromatosis type 2.
Treatment: if solitary, excision. Schwannomas can
often be resected without sacrificing the nerve
of origin, whereas resection of a neurofibroma
usually requires transection of the nerve.
SCHWANNOMA
EPIDEMIOLOGY. The peak incidence of schwanno-
mas is in the third to sixth decades. Men and women
are affected similarly. Schwannomas occur sporadically
or in association with neurofibromatosis type 2 (NF2),
which is discussed in greater detail in Chapter 141).
ETIOLOGY AND PATHOGENESIS. Schwanno-
mas are also called neurinomas, neurolem(m)omas, or
neurilem(m)omas. Mutations in the NF2 gene are the
underlying cause of the schwannomas of both the
sporadic type and NF2. They usually arise in cranial
nerves, especially the vestibular nerve (the so-called
acoustic neuromas are actually schwannomas of the ves-
tibular division of the eighth cranial nerve); they also
occur in other peripheral nerves and spinal roots.
CLINICAL FINDINGS
Cutaneous Lesions. The classic schwannomas
often involve the head and neck. Most schwannomas
are intracranial, intraspinal, or deep soft-tissue lesions.
In the skin, schwannomas present as soft, asymptom-
atic, dermal, or subcutaneous papules or nodules.
They are usually solitary.
Multiple Schwannomas. Neurilemmomatosis or
schwannomatosis presents with multiple cutaneous,
soft-tissue, or spinal schwannomas, but without ves-
tibular schwannomas or other central nervous system
tumors typical of NF2 (such as meningiomas or ependy-
momas). This entity is usually sporadic but can rarely be
familial. Some of these patients may have unrecognized
NF2, either because they have had insufficient cranial
imaging or because they are still too young to exclude
the eventual growth of the tumors.58 Among those in
whom vestibular schwannomas have been definitively
excluded, a minority carry germ-line mutations of the
NF2 gene.58,59 Some patients are in fact somatic mosa-
ics, which could explain the limited extent of their
disease.60 However, the majority of schwannomatosis
patients (including those with the familial form) do not
have germ-line mutations of NF2, even though their
schwannomas do harbor the typical somatic mutations
seen in NF2-associated schwannomas. It has been sur-
mised that this type of schwannomatosis is due to an
inheritable predisposition to somatic NF2 mutations.60
Finally, a last group of patients has neither germ-line
nor somatic NF2 mutations; in these individuals, an as
yet unknown gene may be involved.57
HISTOPATHOLOGY. Because a schwannoma is a
neoplastic proliferation composed only of Schwann
cells and devoid of axons, it grows as an eccentric nod-
ule, displacing its nerve of origin. This growth pattern
and its cellular composition distinguish schwannoma
from neurofibroma (Fig. 127-6).
Schwannomas are well encapsulated. The capsule
is derived from the epineurium of the schwannomas
nerve of origin. The tumor cells are typically slender,
spindled, elongated, and wavy in appearance. Areas
of high cellularity (called Antoni A) alternate with
areas of hypocellularity (Antoni B), which can have a
myxoid quality. In the cellular Antoni A areas, adjacent
cells have a tendency to align, creating stacks of nuclei
known as palisades. These palisades are separated by an
anuclear area made up of stacked cytoplasmic exten-
sions; these stacks of nuclei and cell processes form the
so-called Verocay bodies (see Fig. 127-6). Tumor blood
vessels are characteristically thick and hyalinized.
By immunohistochemistry, schwannomas are
strongly positive for S100 protein and negative for
EMA and smooth muscle markers (desmin, -actin),
23
Chapter 127
Figure 127-6 Photomicrograph of a schwannoma showing
orderly arrangement of tumor cells into palisades and Vero-
cay bodies. (Hematoxylin and eosin, 100.)
which distinguishes them from perineuromas (S100
negative, EMA positive, desmin and -actin negative)
::
and leiomyomas (S100 and EMA negative, desmin and
Neoplasias and Hyperplasias of Muscular and Neural Origin
-actin positive) (see Table 127-1).
Several histologic variants of schwannoma are rec-
ognized.61 Some tumors have extensive degeneration
with cyst formation, old hemorrhage, and marked
hyalinization (ancient schwannoma). This may be
accompanied by bizarre nuclear morphology that does
not imply malignancy. Other schwannomas are cellu-
lar with few hypocellular areas and few palisades or
Verocay bodies. These tumors have been called cellular
schwannomas.62 They may have significant mitotic activ-
ity but behave in a benign fashion. A rare and unusual
variant is the melanotic schwannoma and contains
concentrically lamellated microcalcifications called
psammoma bodies. Although this psammomatous mela-
notic schwannoma only rarely involves the skin, it is
noteworthy that roughly one-half the affected patients
have Carney syndrome (myxomas, spotty hyperpig-
mentation, endocrine overactivities, and schwanno-
mas)52 and approximately 10% of cases metastasize.63
The plexiform schwannoma is a tumor that grows
within a nerve, forming an agglomeration of small nod-
ules and interconnected cords. Plexiform schwanno-
mas have a distinct predilection for the dermis and
subcutaneous tissue. The relationship between plexi-
form schwannoma and NF is somewhat ill defined,
because of confusing nomenclature and because some
authors do not distinguish between NF1 and NF2.
Some solitary, and, especially, multiple plexiform
schwannomas can be associated with NF2.64,65
DIFFERENTIAL DIAGNOSIS. Differential diagno-
sis of schwannomas includes lipoma, cyst, leiomyoma,
and malignant peripheral nerve sheath tumor (MPNST).
TREATMENT. Malignant transformation of clas-
sic schwannomas is exceedingly rare but has been
reported. Excision is the treatment of choice. Plexiform
schwannomas may recur, but this probably reflects
incomplete excision due to their multifocal nature
rather than true recurrence. Pregnancy does not alter
the natural history of schwannomas.66 1477
23 NEUROFIBROMA
EPIDEMIOLOGY. Neurofibromas often occur as
solitary lesions and are common in the general popu-
lation. NF1 has a prevalence of 1 in 4,000.67
ETIOLOGY AND PATHOGENESIS. Neurofi-
bromas are hyperplasias of all the nerves elements.68
Neurofibromas can be seen as sporadic lesions or in
the context of NF1, which is covered in detail in Chap-
ter 141. The gene for NF1 is located on the long arm of
chromosome 17 (17q11.2). At least one of the functions
of the NF1 protein, neurofibromin, is regulation of the
ras oncogene.6971 Although it has been shown that
Section 23 ::
ablating NF1 in mice can lead to the development of
neurofibromas,72 the effects on the levels of ras are not
consistent and, thus, other stromal or genetic effects
must contribute to the development of neurofibromas.
CLINICAL FINDINGS. Cutaneous neurofibromas
Tumors and Hyperplasias of the Dermis and Subcutaneous Fat
present as protuberant to pedunculated, flesh-colored,
soft papules or nodules. They are usually asymptom-
atic, but they can be pruritic. Subcutaneous neuro-
fibromas are usually larger than dermal lesions and
consist of a fusiform swelling involving a larger nerve.
In patients with NF1, the tumors start appearing in
early childhood and may be quite variable in size.
NF1 has a highly variable expressivity, even among
patients from the same kindred who have identical
germ-line mutations.73 Another type of neurofibroma
is the plexiform variant (Fig. 127-7), which involves an
entire large nerve and its branches, forming a mass of
tangled, rope-like structures that feel similar to a bag
of worms on palpation and can be associated with
Figure 127-7 Plexiform neurofibroma on the arm. The
excoriations show the pruritus associated with these
lesions. (Photo from the collection of Dr. Amy Paller, MD,
1478 Childrens Memorial Hospital, Chicago, IL.)
massive soft-tissue overgrowth, leading to functional
impairment.
HISTOPATHOLOGY. Histologically, a neurofi-
broma is composed of Schwann cells, fibroblasts,
endothelial cells, perineurial fibroblasts, mast cells,
and axons, all arranged haphazardly in a matrix that
contains collagen and myxoid ground substance
in various proportions. Dermal neurofibromas are
circumscribed but unencapsulated nodules. A rare
subtype of neurofibroma is the diffuse variant that
involves the skin and subcutaneous tissue in a plaque-
like fashion, surrounding rather than displacing pre-
existing structures such as skin appendages. Plexiform
neurofibromas have the same histologic appearance
as ordinary neurofibromas but involve an entire nerve
and its branches; they also infiltrate the surrounding
soft tissue. A variant with a very unusual histologic
appearance has been described as dendritic cell neuro-
fibroma with pseudorosettes.74 Finally, some neurofibro-
mas are melanotic.
DIFFERENTIAL DIAGNOSIS. Differential diag-
nosis of neurofibroma includes fibrolipoma, lipoma,
and MPNST.
TREATMENT. Solitary dermal neurofibromas can
be excised. Management of patients with NF175 is
discussed in Chapter 141. Resection is currently the
best treatment option for plexiform neurofibromas;
however, the lesions frequently recur after resection.
Recurrence is more commonly associated with a young
patient age, incomplete tumor resection, or nonextrem-
ity tumor location.76
MALIGNANT TUMORS OF NERVE
MALIGNANT NERVE SHEATH TUMORS
MALIGNANT NERVE SHEATH
TUMORS AT A GLANCE
Malignant nerve sheath tumors are also known
as neurofibrosarcoma, neurogenic sarcoma,
neurosarcoma or malignant schwannoma.
Two percent of nerve sheath tumors are
malignant peripheral nerve sheath tumors
(MPNSTs).
Twenty percent to 70% of MPNSTs occur in
neurofibromatosis type 1.
Clinical presentation: nodules in the deep
soft tissues.
Treatment: surgical.
Outcome: guarded, with 5-year survival rates
of not more than 50%.
EPIDEMIOLOGY. Only 2% of nerve sheath tumors are
MPNSTs.91 Depending on the series, approximately 20%
70% of MPNSTs occur in patients with NF1.71 Young and
middle-aged adults are most commonly affected.
ETIOLOGY AND PATHOGENESIS. MPNST is
also known as neurofibrosarcoma, neurogenic sarcoma,
neurosarcoma, and malignant schwannoma, but because
its histogenesis is uncertain, the noncommittal term
MPNST is preferred. Plexiform neurofibromas and neu-
rofibromas involving medium-sized to large nerves can
undergo malignant degeneration into MPNSTs. Benign
schwannomas and cutaneous neurofibromas, on the
other hand, almost never undergo malignant transfor-
mation. There have been very few cases reported.92
CLINICAL FINDINGS. These neoplasms arise
mostly in the deep, soft tissues as nodules. Primary
cutaneous MPNSTs are rare.93,94
HISTOPATHOLOGY. MPNSTs often have a rela-
tively nonspecific presentation of interlacing bundles
of spindle cells. Most tumors consist of perineural or
endoneural fibroblasts.95 Often, the major reason for
calling such a tumor MPNST is that it arises within
a nerve or a neurofibroma and shows some immu-
noreactivity for S100 protein.96 In addition to S100
staining, MPNSTs can also stain for neuron-specific
enolase, neurofilament protein, and myelin basic pro-
tein, although staining can be very weak (see Table
127-1). Cytokeratin stains are negative. MPNSTs
can contain heterologous components such as bone,
cartilage, glandular or squamous epithelium, and
skeletal muscle. An MPNST with a rhabdomyosarco-
matous component is called a malignant triton tumor
and stain positive for myoglobin. In some MPNSTs,
the tumor cells have an epithelioid appearance, and
this variant must be distinguished from melanoma.97
DIFFERENTIAL DIAGNOSIS. Differential diagno-
sis of MPNSTs includes neurofibroma, lipoma, and cyst.
TREATMENT. MPNSTs in patients with NF are
aggressive tumors with a tendency to recur and metas-
tasize. Treatment is surgical. Outcome is guarded
with reported 5-year survival rates of no more than
50% in spite of aggressive therapy.71 Primary cutane-
ous MPNSTs may have a better prognosis.93,94
MISCELLANEOUS TUMORS
GRANULAR CELL TUMOR
GRANULAR CELL TUMOR AT A GLANCE
S100 positive; suspected to be of neural crest origin.
Most common single anatomic site: tongue.
Forty-four percent occur in skin.
Treatment: excision.
EPIDEMIOLOGY. GCTs are rare. The age range at
23
presentation is usually from the second through the
sixth decades.103
ETIOLOGY AND PATHOGENESIS. GCTs may
also be referred to as Abrikossoff tumors. GCTs are neo-
plasms of uncertain histogenesis, but due to the S100
staining, current opinion favors neural crest origin.104
The etiology is unknown, but they have been attrib-
uted to chronic trauma.103
CLINICAL FINDINGS. GCTs have been reported
in many anatomic sites but are most often seen in the
tongue and skin. The tongue is the most common single
anatomic site reported; however, 44% of GCTs occurred
Chapter 127
in skin or subcutaneous tissue. GCTs have also been
reported in the breast, genitalia, esophagus, and larynx.103
Multiple GCTs are seen in approximately 10%25% of
affected patients.104 Most cutaneous GCTs are asymptom-
atic papules or nodules smaller than 3 cm in diameter.
::
HISTOPATHOLOGY. The classical histologic pic-
Neoplasias and Hyperplasias of Muscular and Neural Origin
ture is that of an ill-defined, dermal, nonencapsulated
nodule composed of large, polyhedral cells that grow
in a sheet-like fashion. The cells have distinct cell bor-
ders, small, round, central nuclei, and abundant gran-
ular cytoplasm (Fig. 127-8). The cytoplasmic granules
stain strongly with the periodic acid-Schiff stain and
retain this characteristic after diastase digestion. By
immunohistochemistry, the granular cells are strongly
positive for S100 protein (see Table 127-1). When dif-
ferentiating from melanoma, HMB-45 expression is
100% specific for the diagnosis of melanoma. Rare
cases of GCT show focal Melan-A positivity, similar
to melanoma.105 Ultrastructurally, the granules consist
of phagolysosomes containing granular and membra-
nous debris.104 An unusual plexiform variant has been
described.106 Cutaneous and mucosal lesions typically
have pseudoepitheliomatous hyperplasia of the over-
lying epithelium.
Only 1%2% of GCTs are malignant.104 Clinical find-
ings that should raise concern are a size larger than
Figure 127-8 Histologic examination of granular cell
tumor. The cells have distinct cell borders; small, round,
central nuclei; and abundant granular cytoplasm. (Hema-
toxylin and eosin, 400.) 1479
23 45 cm, location in deep soft tissue, and recurrence.
Histologic warning signs are the presence of increased
cellularity, cytologic atypia, and especially mitotic fig-
ures and necrosis. However, some clinically malignant
GCTs were small and/or histologically innocuous.104
Therefore, the only definite proof of malignancy is
metastasis. Other malignant cutaneous tumors that
can contain a subpopulation of cells with granular
cytoplasm, such as leiomyosarcoma, melanoma, or
angiosarcoma have to be excluded pathologically.
DIFFERENTIAL DIAGNOSIS. Differential diag-
nosis of GCTs includes squamous cell carcinoma of the
tongue, leiomyosarcoma, melanoma, and angiosarcoma.
Section 23 ::
TREATMENT. Excision is the treatment of choice.
NEUROGLIAL HETEROTOPIA
NEUROGLIAL HETEROTOPIA
AT A GLANCE
Tumors and Hyperplasias of the Dermis and Subcutaneous Fat
Rare congenital lesion commonly referred to
as nasal glioma.
Developmental anomaly consists of mature
displaced neuroglial tissue; not a true neoplasm.
Presentation: most commonly as round, firm
papule on the nose.
Rarely connected to intracranial cavity.
MENINGEAL HETEROTOPIA
MENINGEAL HETEROTOPIA
AT A GLANCE
Rare lesion characterized by meningothelial
elements in skin.
Occurs in children secondary to developmental
defect; occurs in adults secondary to extension
of intracranial meningioma.
Can be connected to intracranial cavity.
1480
CUTANEOUS GANGLIONEUROMA
AND GANGLION CELL TUMOR
Ganglioneuromas are neoplasms composed of
large mature neurons (ganglion cells) growing in
a Schwann cell stroma. Pure ganglion cell tumors
(or gangliocyto-mas) do not contain the Schwann
cell component. Although they are usually seen as
tumors of the autonomic nervous system, some very
rare examples have been encountered in the skin or
subcutis where they presented as small papules or
nodules. Of the half dozen or so reported cases,114,115
only one was congenital.115 These lesions have to
be distinguished from cutaneous metastases from a
neuroblastoma, which can mature into ganglioneu-
roma. Furthermore, some plexiform neurofibromas
in patients with NF arise in autonomic ganglia and
can therefore contain residual, entrapped ganglion
cells.116
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