Common Diagnostic Dilemmas in Bone and Soft Tissue Surgical Pathology
Case 7 -
The patient is a 41-year-old male with a
painful, posterior calf mass.
Nerve sheath tumors, especially benign forms, are fairly common neoplasms occurring in virtually all
anatomic compartments and sites. Outside of neurofibromatosis, the vast majority of the deeply-seated
lesions are schwannomas (neurilemomas); neurofibromas generally present as solitary cutaneous masses and
are rarely observed within the deep soft tissues of the extremities, thorax, or abdomen. Most
pathologists are fairly familiar with the histology of neurofibroma and schwannoma; however, there are
some important points worth reviewing.
Schwannomas are well-circumscribed and encapsulated masses that usually arise as eccentric, sometimes
dumbbell-shaped lesions of peripheral nerve, most commonly occurring in the extremities and head and neck
region. Most patients are between 20 and 50 years of age at diagnosis. Common complaints include the
presence of a slow growing painful tumor associated with neurologic symptoms. Head and neck lesions may
be associated with headache, epistaxis, or otitis media. As previously mentioned, they are only rarely
cutaneous and almost always solitary. Multiple tumors may be associated with Neurofibromatosis, type
2.  Microscopically, the histologic hallmark of schwannomas is the alternating Antoni A
(cellular and compact spindle cell proliferation arranged in bundles and intersecting fascicles) and
Antoni B (hypocellular spindle cells proliferation arranged haphazardly within a loose matrix) regions.
Nuclear palisading and so-called Verocay bodies are often observed in the Antoni A areas, while
microcystic change and inflammatory cells are usually evident in the Antoni B zones. Another helpful
feature is the presence of hyalinized blood vessels. Atypia in the form of ancient change is often
present and may be widespread, but the degree of atypia exceeds the expected mitotic activity, which in
degenerative schwannomas is virtually absent. As a general rule, avoid the
diagnosis of malignancy in any spindle cell tumor with moderate to marked atypia but a correspondingly
low mitotic rate. An diagnostic pitfall is cellular schwannoma, a tumor comprised of
predominantly Antoni A, more commonly seen in the paravertebral region of the mediastinum,
retroperitoneum, and pelvis.  Mitotic activity may be quite high and focal necrosis is
occasionally observed. Helpful diagnostic clues include circumscription, the presence of hyalinized
blood vessels, variable numbers of lipid-laden macrophages, and strong and diffuse S-100 protein
positivity. In addition, it is worth remembering that encapsulation may be less evident or lacking
altogether in schwannomas arising in the sinonasal tract and nasopharynx. 
Neurofibromas may present as one of three forms: solitary and circumscribed (most common), diffuse,
and plexiform. The localized form is the most common and typically arises as sporadic, solitary and
cutaneous/subcutaneous lesions in young adults; a minority of cases is associated with neurofibromatosis,
type 1. Such tumors may be found at virtually any anatomic site. Diffuse neurofibromas usually occur as
plague-like skin lesions involving the head and neck regions of children and young adults. Approximately
10% of such cases are associated with neurofibromatosis, type 1.  As the name implies,
diffuse neurofibromas grows as diffuse and infiltrative masses, entrapping but not destroying residual
adnexal structures. Plexiform neurofibromas are virtually pathognomonic of type 1 neurofibromatosis.
Histologically, neurofibromas are unencapsulated and generally arise as fusiform expansions of peripheral
nerve, although this is often not evident in cutaneous tumors. They are typically comprised of
haphazardly arranged Schwann cells accompanied by variable amounts of wire-like strands of collagen,
embedded in at least a partially myxoid stroma. Chronic inflammatory cells and histiocytes are often
randomly distributed throughout the tumor. More cellular tumors appear more compact with less myxoid
matrix, often exhibiting prominent whorls and storiform patterns. Compared to the localized or solitary
type, diffuse neurofibromas have a more uniform matrix of fine fibrillary collagen and diffusely
infiltrate and entrap pre-existing adnexal structures. The Schwann cells are generally shorter but
remain very uniform. Wagner-Meissner bodies or clusters are a characteristic feature. The main
differential diagnosis is dermatofibrosarcoma protuberans; correlation with clinical findings and
judicious use of immunohistochemistry will help avoid a misdiagnosis. Plexiform neurofibromas produce
tortuous expansion of multiple nerve branches, ranging from simply an increase in endoneurial contents to
areas resembling solitary neurofibroma. Over time, the contents of these expanded nerve fibers spills
out into the adjacent skin and soft tissues, creating the appearance of a combined plexiform/diffuse
It is well known that neurofibromas may exhibit clinically insignificant nuclear atypia. Furthermore,
it is also clear that infrequent mitotic activity (<1 mitotic figure/10 high power fields) in
normal-appearing (or even cellular) neurofibromas is of no clinical relevance. Conservative surgical
resection is adequate treatment.  However, diffuse nuclear atypia, increased cellularity
(closely packed tumor cells), and mitotic activity exceeding 1 mitotic figure per 10 high power fields,
especially if accompanied by necrosis, indicate malignant change. When a neurofibroma shows some but not
all of these atypical features, some have proposed the designation of "neurofibroma with atypical
features."  The diagnosis of malignant peripheral nerve sheath tumor (MPNST) usually requires
at least one of the following clinical settings: 1) origin from a peripheral nerve, usually a large
nerve trunk, 2) origin from a pre-existing benign nerve sheath tumor, usually a neurofibroma, and/or 3)
occurrence in a patient with neurofibromatosis. Rarely, the diagnosis may be rendered outside of these
clinical settings, if classic morphologic features are evident. Compared to other spindle cell tumors,
the morphologic diversity of MPNST is quite impressive. Most appear as obvious high grade sarcomas and
manifest features of fibrosarcoma. Surprisingly, classic nuclear palisading is often absent.
Additionally, MPNST may be very heterogeneous, containing elements of glandular differentiation,
rhabdomyosarcoma, bone and/or cartilaginous metaplasia. More anaplastic-appearing forms closely resemble
pleomorphic malignant fibrous histiocytoma.
In difficult cases, the use of S-100 protein, especially in small biopsy specimens, is invaluable.
Strong and diffuse staining for S-100 protein is a hallmark of schwannoma or neurofibroma; patchy and
focal staining for S-100 protein is more typical of MPNST.  Furthermore, up to 50% of cases of
MPNST may be negative for S-100 protein. For these reasons, a spindle cell lesion
with "borderline" malignant features that is strongly and diffusely S-100 protein positive is probably
NOT malignant. Such a tumor is far more likely to represent a schwannoma than a MPNST. Obviously
anaplastic and malignant tumors that are strongly and diffusely S-100 protein positive are far more
likely to represent melanoma than MPNST. A potential pitfall is the presence of keratin
expression, more commonly observed in retroperitoneal forms. 
- Antinheimo J, Sankila R, Carpen O, et al. Population based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology 2000;54:71-76.
- White W, Shiu MH, Rosenblum MK, et al. Cellular schwannoma: a clinicopathologic study of 57 patients and 58 tumors. Cancer 1990;66:1266-1275.
- Hasegawa SL, Mentzel T, Fletcher CDM. Schwannomas of the sinonasal tract and nasopharynx. Mod Pathol 1997;10:777-784.
- Weiss SW, Goldblum JR. Benign Tumors of Peripheral Nerves. In: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, MO. Mosby, 2001:111-1207.
- Lin BTY, Weiss LM, Medeiros LJ. Neurofibroma and cellular neurofibroma with atypia: a report of 14 tumors. Am J Surg Pathol 1997;21:1443-1449.
- Weiss SW, Langloss JM, Enzinger FM. Value of S-100 protein in the diagnosis of soft tissue tumors with particular reference to benign and malignant Schwann cell tumors. Lab Invest 1983;49:299-308.
- Fanburg-Smith JC, Majidi M, Miettinen M. Keratin expression in schwannoma; a study of 115 retroperitoneal and 22 peripheral schwannomas. Mod Pathol 2006;19:115-121.