Chapter 127. Neoplasias and Hyperplasias of Muscular and Neural Origin

The dermis contains smooth muscle fibers in the arrector pili muscles, in the walls of dermal blood vessels, and in the dartos muscle of the scrotum, vulva, nipple, and areola. There are three types of cutaneous smooth muscle lesions: (1) leiomyomas, (2) leiomyosarcomas, and (3) hamartomas. Smooth muscle is recognized histologically by spindle cell shape, eosinophilic, fibrillary cytoplasm, and blunt-ended, oval, “cigar-shaped” nuclei. On immunohistochemical staining, cells express smooth muscle actin and the muscle-specific intermediate filament desmin, but are negative for S100 protein and epithelial membrane antigen (EMA).

Leiomyoma

Epidemiology

The exact incidence of leiomyomas 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 relatively uncommon neoplasms, the actual incidence may be higher than previously believed due to failure to recognize and biopsy the lesion.

Etiology and Pathogenesis

Cutaneous 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, originating from vascular smooth muscle. Most leiomyomas are acquired; however, familial inheritance patterns have been described. Especially noteworthy are patients with multiple piloleiomyomas. Starting in early adulthood, these patients present with increasing numbers of tumors, developing as many as 100–1,000 lesions. Transmission appears to be autosomal dominant with variable penetrance.2 Women with multiple piloleiomyomas may also develop uterine leiomyomas, an entity termed multiple cutaneous and uterine leiomyomatosis (also known as familial leiomyomatosis cutis et uteri or Reed syndrome).2 In addition, some families with multiple cutaneous and uterine leiomyomatosis have been shown to cluster renal cell cancer, and this has been termed hereditary leiomyomatosis and renal cell cancer. Recently, a loss of function mutation in the gene encoding fumarate hydratase on chromosome 1q42.3–43 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

Clinical Findings

The most common presentation 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 dermatomal patterns.5 The extensor extremities, trunk, and sides of the face and neck are the most common locations. Patients with piloleiomyomas often have pain that may be spontaneous or secondary to cold, pressure, or emotion.2,5–7 Possible explanations for this phenomenon include pressure of the tumor on local nerve fibers and contraction of the smooth muscle fibers.5 Genital leiomyomas are clinically similar to piloleiomyomas except that they are usually asymptomatic.5 They commonly present as solitary, deep papulonodules or occasionally, pedunculated papules on the scrotum, vulva, penis, or areolar region. Angioleiomyomas present most commonly as solitary, painful subcutaneous nodules on the legs in women that can grow to several centimeters in diameter.8

Histopathology

Pilar leiomyomas are composed of a poorly circumscribed proliferation of haphazardly 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 leiomyomas. Angioleiomyomas are well-circumscribed, richly vascularized dermal or subcutaneous nodules composed of well-differentiated smooth muscle fibers (Fig. 127-2). Occasionally, the vessel of origin can be identified. Leiomyomas stain positive with smooth-muscle actin and desmin.

Differential Diagnosis

Differential diagnosis of leiomyoma includes any flesh-colored or reddish-brown superficial or deep-seated papule or nodule: angiolipoma, glomus tumor, eccrine spiradenoma, neurofibroma, nevus, or lipoma.

Prognosis and Clinical Course

Cutaneous leiomyomas do not regress spontaneously, and there does not appear to be risk of malignant degeneration 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 demonstrated in tumor extracts.9

Treatment

Excision is the treatment of choice for leiomyomas that cause pain or cosmetic concern; however, recurrence is common. In patients with numerous 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 possible, potential treatment options include nitroglycerin, phenoxybenzamine, nifedipine, gabapentin, intralesional botulinum toxin, or topical analgesics.2,12–15

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

Leiomyosarcoma is a rare, malignant mesenchymal tumor of smooth muscle origin usually found in the uterus, the retroperitoneum, gastrointestinal tract, or deep soft tissue. The term superficial leiomyosarcomas refers to those tumors whose primary site of origin is the skin. Those derived from arrector pili or genital smooth muscles 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.

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 paresthetic. 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 epidermal change. Some patients have multiple grouped lesions; in one series, four of seven such patients had a previous retroperitoneal leiomyosarcoma,18 highlighting the importance of ruling out metastases in patients with numerous superficial leiomyosarcomas.

Histopathology

Leiomyosarcomas are large tumors consisting of smooth muscle fibers arranged in irregular, intersecting bundles and fascicles in the dermis and subcutis, often with infiltrating borders. Tumor cells exhibit smooth muscle differentiation with atypical cytologic features such as nuclear hyperchromasia, prominent nucleoli, mitosis, and necrosis (Fig. 127-3). In less well-differentiated areas, highly pleomorphic and multinucleated cells may be found.5 Granular cell, epithelioid cell, myxoid, and sclerosing (or desmoplastic) 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 carcinoma, 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 diagnosis of leiomyosarcoma includes any solitary, enlarging dermal or subcutaneous nodule: lipoma, dermatofibroma, dermatofibrosarcoma, neurofibroma, spindle cell melanoma, spindle cell squamous cell carcinoma, and atypical fibroxanthoma.

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 subcutaneous leiomyosarcomas.5,9,16,17,22–25 The lung is the most common location of metastasis.

Treatment

Therapy for superficial leiomyosarcoma 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

Epidemiology

First described by Stokes in 1923,27 smooth muscle hamartoma has become increasingly 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 majority 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 hyperpigmentation and hypertrichosis. Vellus hairs may be prominent. Some can produce worm-like movements (vermiculation), and stroking may induce transient induration with piloerection (pseudo-Darier sign). Smooth muscle hamartoma shares some clinical and histologic features with Becker's 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 follicular units. There may be basal layer hyperpigmentation, 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 discrete bundles and the lack of intermingling of these bundles with dermal collagen fibers.

Differential Diagnosis

Differential diagnosis of hamartoma includes congenital nevus, Becker's nevus, café-au-lait macule, leiomyoma, neurofibroma, and solitary mastocytoma.

Prognosis and Clinical Course

Malignant degeneration has not been reported. Although the localized form is usually not associated with other congenital anomalies,29 patients with the generalized form have been reported to have multiple associated congenital 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 include true neoplasms of striated muscle differentiation (rhabdomyomas and rhabdomyosarcomas) as well as non-neoplastic neuromuscular and rhabdomyomatous mesenchymal hamartomas (RMHs).

Rhabdomyoma

Epidemiology

Extracardiac rhabdomyomas are extremely rare and comprise fewer than 2% of striated muscle neoplasms.35 The adult and fetal types of rhabdomyomas 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

Rhabdomyomas are benign tumors of striated muscle. Extracardiac rhabdomyomas are not associated with TS, whereas significant portion of patients with cardiac rhabdomyomas are ultimately diagnosed with TS.

Clinical Findings

Extracardiac rhabdomyomas are subdivided into three types: (1) adult, (2) fetal, and (3) genital.35,37 The designation as adult or fetal refers to the tumor's resemblance to adult or fetal skeletal 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 polypoid vaginal or vulvar lesions in middle-aged women.37

Histopathology

Rhabdomyomas are composed of fascicles of oval and polygonal-shaped cells with eosinophilic, often vacuolar cytoplasm and eccentrically placed nuclei.35 Atypia, mitosis, and pleomorphism are absent.

Differential Diagnosis

Differential diagnosis of rhabdomyomas includes granular cell tumor (GCT), hibernoma, and reticulohistiocytoma.

Prognosis and Clinical Course

Extracardiac and cardiac rhabdomyomas have a very low risk of malignant degeneration. Many cardiac rhabdomyomas regress spontaneously with age.

Treatment

The treatment of choice for symptomatic extracardiac rhabdomyomas is surgical excision.

Rhabdomyosarcoma

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.38–40 Only approximately 0.7% occur as primary skin lesions.40 Males are more commonly affected than females.38

Etiology and Pathogenesis

Rhabdomyosarcomas are malignant neoplasms derived from skeletal 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 rhabdomyosarcoma is characterized at the molecular level by novel fusion genes combining the forkhead (FKHR) gene with either the PAX3 or the PAX7 gene, producing a t(2;13)(q35;q14) or t(1;13)(p36;q14), respectively.38

Clinical Findings

Cutaneous rhabdomyosarcoma 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 composed of sheets of pleomorphic, small blue cells infiltrating the dermis and subcutaneous tissue. High mitotic index is present, and focal areas of necrosis can often be identified.41 The embryonic type is composed 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 differentiating rhabdomyosarcoma from other “small blue cell tumors.” Rhabdomyosarcomas express positivity for muscle-specific actin, desmin, myoD1, and myogenin. Reverse transcription polymerase chain reaction and fluorescence in situ hybridization analysis can used to detect the t(2;13)(q35;q14) and t(1;13)(p36;q14) chromosomal translocations.38,41

Differential Diagnosis

Differential diagnosis of rhabdomyosarcoma includes hemangioma, hematoma, neuroblastoma, and other soft-tissue sarcomas.

Prognosis and Clinical Course

Prognosis is poor, with many patients succumbing to their disease. Even with appropriate treatment, rhabdomyosarcomas can recur and metastasize to regional lymph nodes, lung, bone, and heart. Congenital alveolar rhabdomyosarcoma has an especially poor prognosis; there are no reports in the literature of survivors.38

Treatment

Treatment of rhabdomyosarcoma consists of a combination of surgical excision, chemotherapy, and radiotherapy.

Neuromuscular Hamartoma

Rhabdomyomatous Mesenchymal Hamartoma

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 fibroblasts, called a traumatic neuroma. Within the bundle of nerves and fibroblasts, the axons can begin to synapse and send pain signals. These signals occur spontaneously 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 haphazardly arranged. A fibrous or collagen sheath may surround neuromas, but these neuromas are not encapsulated by perineurium. The neuromas stain for EMA. Staining of the neural lesions is reviewed in Table 127-1.

Differential Diagnosis

Differential diagnosis of neuromas includes hypertrophic scar, dermatofibroma, digital fibrokeratoma, and verruca vulgaris.

Treatment

Temporary pain relief can be achieved with a local anesthetic nerve block. For more permanent pain relief, surgical treatment aims either at isolating the nerve from injury or excising the neuroma.46

Palisaded Encapsulated Neuroma

Epidemiology

Palisaded encapsulated neuromas (PENs) present in adults, mostly in their third to fifth decade. There appears to be no gender predilection. 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 asymptomatic, flesh-colored papules or nodules that are smaller than 1 cm in diameter. PENs are located on the face in approximately 80% of cases.47 PEN is almost never diagnosed clinically; the most common misdiagnoses are dermal melanocytic nevus, basal cell carcinoma, and adnexal tumor.

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 typical of schwannomas is often indistinct. Special stains demonstrate variable numbers of axons within the lesion. The capsule often stains with EMA, suggesting 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 schwannomas that contain a few residual entrapped axons.51

Differential Diagnosis

Differential diagnosis 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 multiple endocrine neoplasia syndrome type 2B (MEN2B; see Section “Mucosal Neuromas and Multiple Endocrine 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 addition, 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 affected individuals in MEN2B families.53 The neuromas involve all mucosal surfaces (oral mucosa, lips, tongue, and conjunctivae) and appear as pink, pedunculated papules or nodules. The lips become enlarged and bulging, and the eyelids may be everted. Other cutaneous lesions include café-au-lait spots, facial lentigines, and hyperpigmentation of the hands and feet.

Histopathology

Histologically, there is hypertrophy of the mucosal nerves; some lesions may resemble PENs.

Differential Diagnosis

Differential diagnosis 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 thyroidectomy by 5 years of age are essential.53

Morton Neuroma

Hyperplastic/Hypertrophic Pacinian Corpuscle

Schwannoma

Epidemiology

The peak incidence of schwannomas 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

Schwannomas 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 vestibular 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, asymptomatic, 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 vestibular schwannomas or other central nervous system tumors typical of NF2 (such as meningiomas or ependymomas). 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 mosaics, 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 surmised 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 nodule, 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 schwannoma's 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 extensions; 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, α-actin), which distinguishes them from perineuromas (S100 negative, EMA positive, desmin and α-actin negative) and leiomyomas (S100 and EMA negative, desmin and α-actin positive) (see Table 127-1).

Several histologic variants of schwannoma are recognized.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 cellular with few hypocellular areas and few palisades or Verocay bodies. These tumors have been called cellular schwannomas.62 They may have significant mitotic activity 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 melanotic schwannoma only rarely involves the skin, it is noteworthy that roughly one-half the affected patients have Carney syndrome (myxomas, spotty hyperpigmentation, endocrine overactivities, and schwannomas)52 and approximately 10% of cases metastasize.63

The plexiform schwannoma is a tumor that grows within a nerve, forming an agglomeration of small nodules and interconnected cords. Plexiform schwannomas have a distinct predilection for the dermis and subcutaneous tissue. The relationship between plexiform 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 diagnosis of schwannomas includes lipoma, cyst, leiomyoma, and malignant peripheral nerve sheath tumor (MPNST).

Treatment

Malignant transformation of classic 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

Neurofibroma

Epidemiology

Neurofibromas often occur as solitary lesions and are common in the general population. NF1 has a prevalence of 1 in 4,000.67

Etiology and Pathogenesis

Neurofibromas 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 Chapter 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.69–71 Although it has been shown that 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 present as protuberant to pedunculated, flesh-colored, soft papules or nodules. They are usually asymptomatic, but they can be pruritic. Subcutaneous neurofibromas 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 massive soft-tissue overgrowth, leading to functional impairment.

Histopathology

Histologically, a neurofibroma 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 preexisting 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 neurofibroma with pseudorosettes.74 Finally, some neurofibromas are melanotic.

Differential Diagnosis

Differential diagnosis 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 nonextremity tumor location.76

Neurothekeoma/Nerve Sheath Myxoma

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Cutaneous Lesions

Histopathology

Differential Diagnosis

Treatment

Perineuroma

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Histopathology

Differential Diagnosis

Treatment

Malignant Nerve Sheath Tumors

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 neurofibromas 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 transformation. 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 relatively 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 immunoreactivity for S100 protein.96 In addition to S100 staining, MPNSTs can also stain for neuron-specific enolase, neurofilament protein, and myelin basic protein, 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 rhabdomyosarcomatous 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 diagnosis of MPNSTs includes neurofibroma, lipoma, and cyst.

Treatment

MPNSTs in patients with NF are aggressive tumors with a tendency to recur and metastasize. Treatment is surgical. Outcome is guarded with reported 5-year survival rates of no more than 50% in spite of aggressive therapy.71 Primary cutaneous MPNSTs may have a better prognosis.93,94

Primitive Neuroectodermal Tumor

Epidemiology, Etiology, and Pathogenesis

Clinical Findings: Cutaneous Lesions

Histopathology

Differential Diagnosis

Treatment

Granular Cell Tumor

Epidemiology

GCTs are rare. The age range at 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 neoplasms of uncertain histogenesis, but due to the S100 staining, current opinion favors neural crest origin.104 The etiology is unknown, but they have been attributed 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 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 asymptomatic papules or nodules smaller than 3 cm in diameter.

Histopathology

The classical histologic picture 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 borders, small, round, central nuclei, and abundant granular 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 differentiating 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 membranous debris.104 An unusual plexiform variant has been described.106 Cutaneous and mucosal lesions typically have pseudoepitheliomatous hyperplasia of the overlying epithelium.

Only 1%–2% of GCTs are malignant.104 Clinical findings that should raise concern are a size larger than 4–5 cm, location in deep soft tissue, and recurrence. Histologic warning signs are the presence of increased cellularity, cytologic atypia, and especially mitotic figures 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 diagnosis of GCTs includes squamous cell carcinoma of the tongue, leiomyosarcoma, melanoma, and angiosarcoma.

Treatment

Excision is the treatment of choice.

Central Nervous System Heterotopia

Neuroglial Heterotopia

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Histopathology

Differential Diagnosis

Prognosis and Clinical Course

Treatment

Meningeal Heterotopia

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Histopathology

Differential Diagnosis

Prognosis and Clinical Course

Treatment

Myxopapillary Ependymoma

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 ganglioneuroma. Furthermore, some plexiform neurofibromas in patients with NF arise in autonomic ganglia and can therefore contain residual, entrapped ganglion cells.116