This soft tissue tumor is derived from the nerve sheath cells. The pathologist has long recognized two major histologic types, a myxoid hypocellular type and a cellular type. The presence of tumors with intermediate features linked these two variants for many years. Recently, immunohistochemical studies performed by pathologists have suggested that these two variants may indeed be two different tumor types. As further evidence, there appears to be a different patient profile for both tumor types (see outline below). The cellular tumors are more common on the head and neck and upper extremities while the myxoid tumors are more common on the trunk and lower extremities.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Nerve sheath myxoma
Neurothekeoma of Gallager and Helwig
AGE RANGE-MEDIAN Cellular Peak 2nd decade Myxoid Peak 3rd decade SEX (M:F) Cellular Male:female 4:7 Myxoid 6:5
PATHOGENESIS CHARACTERIZATION Nerve sheath derivation Myxoid tumors shows nerve sheath differentiation while cellular tumors lack this differentiation
Studies on the cellular origin of neurothekeoma: clinical, light microscopic, immunohistochemical, and ultrastructural observations.
Barnhill RL, Dickersin GR, Nickeleit V, Bhan AK, Muhlbauer JE, Phillips ME, Mihm MC Jr.
Dermatopathology Division, Massachusetts General Hospital, Boston.
J Am Acad Dermatol 1991 Jul;25(1 Pt 1):80-8 Abstract quote
The clinical, histopathologic, and immunohistochemical features of 11 cases of neurothekeoma are reported. One case was examined by electron microscopy. The mean age of the patients was 27.1 years; the study comprised eight female and three male patients. Most lesions were nondescript papules and located on the upper part of the body, seven cases of neurothekeoma on the head.
Eight cases were classified as cellular neurothekeoma on the basis of a striking fascicular pattern and three cases as myxomatous neurothekeoma because of prominent myxoid stromal change. All cellular neurothekeomas failed to express S-100 protein, whereas the three myxomatous types were strongly positive for this marker. Other than vimentin, there was no significant immunoreactivity with other immunohistochemical markers. Ultrastructural study of one case of cellular neurothekeoma was inconclusive for cell type although a perineurial origin could not be excluded.
On the basis of these results, we conclude that cellular neurothekeoma differs from myxomatous neurothekeoma not only by clinical and histologic findings but also by immunoreactivity with S-100 protein. These findings also suggest the existence of two distinct subtypes of neurothekeoma and possible origin of the two variants of neurothekeoma from different cell types or at least variation in phenotypic expression of a common cell type. On the other hand, it cannot be excluded that these two variants are different stages in the natural history of neurothekeoma.
CLINICAL OR GROSS VARIANTS CHARACTERIZATION HEAD AND NECK
Neurothekeoma palpebrae: a rare nerve sheath tumor arising in the eyelid.
You TT, Kaiser PK, Netland TP, Jakobiec FA.
Pacific ClearVision Institute, Eugene, Oregon, USA.
Ophthal Plast Reconstr Surg 1999 Nov;15(6):448-9 Abstract quote
PURPOSE: To report a case of an eyelid neurothekeoma, a rare peripheral nerve sheath tumor.
METHODS: Case report.
RESULTS: An excisional biopsy, performed on a lesion removed from the upper eyelid of a 76-year-old woman, revealed the clinical and histopathologic features of a neurothekeoma, a tumor consisting of multiple collections of spindle cells in a myxomatous background. Immunohistochemical characterization showed positivity for NK1/C3, neuron-specific enolase, and alcian blue.
CONCLUSION: Neurothekeoma palpebrae should be considered in the differential diagnosis of solitary nodules of the eyelids.
Nerve sheath myxoma (neurothekeoma) in the tongue of a newborn.
Penarrocha M, Bonet J, Minguez JM, Vera F.
Oral Medicine, School of Dentistry, Valencia University, Valencia, Spain.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000 Jul;90(1):74-7 Abstract quote
Nerve sheath myxoma is a benign peripheral nerve sheath tumor that rarely occurs in the oral cavity; experience with these lesions is therefore limited. The lesion described in this report appeared clinically as a gradually enlarging, painless growth arising on the tongue of a newborn girl.
Microscopically, the lesion was characterized by nodules of spindle-shaped cells with abundant myxoid stroma. Immunohistochemical studies were consistent with a nerve sheath neoplasm.
Cellular neurothekeoma of the oral mucosa.
Barrett AW, Suhr M.
Department of Oral Pathology, Eastman Dental Institute for Oral Healthcare Sciences, University College London, 256 Grays Inn Road, London WC1X 8LD, UK.
Oral Oncol 2001 Dec;37(8):660-4 Abstract quote
Cellular neurothekeoma is an unusual benign neoplasm which, despite its name, is of uncertain origin. This report describes a cellular neurothekeoma of the cheek mucosa, the first at this site. The tumour presented in a 29-year-old man as a discrete mucosal thickening.
Histology showed a generally well circumscribed, but unencapsulated, solid tumour which replaced the entire lamina propria and permeated between minor salivary glands and bundles of striated muscle in the submucosa. There was a sub-epithelial Grenz zone. The tumour was composed of nodules of pale, epithelioid cells separated by fascicles of spindle cells, with smaller strands and nests superficially. The nuclei were vesicular and, though mainly bland, occasionally atypical. The stroma was moderately infiltrated by mixed chronic inflammatory cells. Prominent nerves and blood vessels were seen at the periphery of the lesion, and neoplastic cells were noted within intact striated muscle fascicles.
With immunohistochemistry, all the neoplastic cells strongly expressed NKI/C3, synaptophysin, neurone-specific enolase and vimentin, some expressed smooth muscle actin and PGP 9.5, but all were negative for S100, factor XIIIa, CD34, CD56, CD57, CD68, chromogranin A, desmin, epithelial membrane antigen and von Willebrand factor. The origin of the lesion is thus speculative. It was, however, completely excised and in 12 months there has been no recurrence
Neurothekeoma of the paranasal sinuses in a 3-year-old boy.
Wong BY, Hui Y, Lam KY, Wei WI.
Department of Otorhinolaryngology, Division of Otorhinolaryngology Head and Neck Surgery, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, SAR, Hong Kong, People's Republic of China.
Int J Pediatr Otorhinolaryngol 2002 Jan 11;62(1):69-73 Abstract quote
Neurothekeoma is a benign soft tissue tumor commonly located on the skin. In this report, a 3-year-old boy presented with restricted right eye movement and decrease in visual acuity. The patient was found to have a 6-cm neurothekeoma involving the maxillary and ethmoid sinuses.
To our knowledge, this is the first reported case of neurothekeoma with involvement of the maxillary and ethmoid sinuses. This uncommon lesion should be considered as the differential diagnosis of pediatric soft tissue tumors in the head and neck region.
Intracranial neurothekeoma--a rare parenchymal nerve sheath myxoma of the middle cranial fossa.
Pal L, Bansal K, Behari S, Sagar BC, Gupta RK, Gupta RK, Shankar SK.
Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Clin Neuropathol 2002 Mar-Apr;21(2):47-51 Abstract quote
Neurothekeomas are rare, benign nerve sheath tumors, usually arising from cutaneous nerves in the head and neck region. So far, only 4 cases of the intracranial counterpart have been reported and these were located in the posterior fossa, sellar and parasellar region.
We report here the first case of neurothekeoma located deep inside the brain parenchyma. Histologically, the tumor had lobular appearance with bland morphology in spite of cellular pleomorphism, myxoid background and variable S-100 positivity, characteristics of neurothekeomas. The schwannian origin was further confirmed ultrastructurally by demonstrating basal lamina and Luse bodies. Because of its benign nature, the lesion does not need postoperative radiotherapy. Histogenesis of neurothekeoma arising in the parenchyma remains enigmatic.
The probable cell of origin could be the Schwann cell or perineurial cell of the nerve twigs around the blood vessels or by extreme differentiation of the precursor cell resting in a suitable microenvironment to the schwannian phenotype.
- Subungual neurothekeoma.
Connolly M, Hickey JR, Intzedy L, Pawade J, de Berker DA.
Department of Dermatology, Bristol Royal Infirmary, United Kingdom.
J Am Acad Dermatol. 2005 Jan;52(1):159-62. Abstract quote
Neurothekeomas are benign tumors probably of nerve sheath origin and are also known as dermal nerve sheath myxomas. They are commonly found on the face, arm, or shoulder and less frequently the lower limbs.
To our knowledge, this is the first case of a subungual neurothekeoma affecting the big toe. Histology confirmed a well-circumscribed, multilobulated tumor composed of bland stellate and spindle cells in a copious myxoid matrix staining positive with S100 protein.
HISTOLOGICAL TYPES CHARACTERIZATION General
Nerve sheath myxoma (neurothekeoma) of the skin: light microscopic and immunohistochemical reappraisal of the cellular variant.
Argenyi ZB, LeBoit PE, Santa Cruz D, Swanson PE, Kutzner H.
Department of Pathology, University of Iowa, Iowa City.
J Cutan Pathol 1993 Aug;20(4):294-303 Abstract quote
Nerve sheath myxoma (NSM) is a rare cutaneous neoplasm, the histogenesis of which is controversial. Fifteen cases of NSM were studied by routine light microscopy and with a broad panel of immunohistochemical stains.
NSM were classified into three groups based on cellularity, mucin content and growth pattern. 1) The hypocellular (myxoid) type (5/15 cases) showed frequent encapsulation or sharp circumscription. Immunohistochemically this type was strongly positive for S-100 protein and collagen type IV and variably positive for epithelial membrane antigen. 2) The cellular type (4/15 cases) had scant mucin and ill-defined nodular or infiltrating growth. Immunostaining showed positive reaction for neuron specific enolase (2/4), Leu-7 (1/4) and smooth muscle specific actin (2/4), and was negative with the other antibodies. 3) The "mixed type" (6/15 cases) had variable cellularity and mucin content with poor demarcation and variable immunolabeling.
We conclude that: 1) there are major light microscopic and immunohistochemical differences between the classical hypocellular (myxoid) and the cellular forms of NSM (neurothekeoma); 2) while the immunohistochemical results support the presence of nerve sheath differentiation in the classical forms of NSM, and to some extent in the mixed forms, there is an absence of convincing evidence of neural differentiation in the cellular variant by either light microscopy or immunohistochemistry; 3) the variable immunophenotypes suggest that differentiation other than neural may take place in CNT.
Atypical or worrisome features in cellular neurothekeoma: a study of 10 cases.
Busam KJ, Mentzel T, Colpaert C, Barnhill RL, Fletcher CD.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Am J Surg Pathol 1998 Sep;22(9):1067-72 Abstract quote
Cellular neurothekeoma is a recently characterized benign cutaneous neoplasm arising usually on the upper trunk or head and neck of children or young adults. Typical histology is that of a lobulated dermal tumor composed of spindle and epithelioid cells, arranged in fascicles and nests, lacking immunoreactivity for S-100 protein, but usually being NK1/C3 positive.
We present 10 new cases of cellular neurothekeoma with atypical histologic features that have not been described previously and that suggested the possibility of malignancy. The age range of affected patients was 1 to 44 years (median, 20.5 years); sites included the head and neck (three cases), the upper limbs (two cases), the lower limbs (two cases), and the trunk (two cases). Atypical findings in individual cases included large size (up to 6 cm), deep penetration (extending into skeletal muscle or subcutaneous fat, or both), diffusely infiltrative borders, vascular invasion, high mitotic rate, and marked cytologic pleomorphism.
Clinical follow-up was available in 7 of 10 cases. Although the atypical features raised concern about the biologic potential of these lesions, preliminary follow-up (1-5 years) has shown no recurrence and suggests that complete surgical excision of these lesions is curative. These new data expand the morphologic spectrum of cellular neurothekeoma.
J Dermatol Surg Oncol 1986 Sep;12(9):958-60 Abstract quote
A 10-mm, asymptomatic, slowly growing, dermal nodule was present on the ankle of a 62-year-old man for 6 months.
Histologically, the nodule was shown to be a neurothekeoma, a recently described benign cutaneous tumor of nerve sheath origin distinct from neurofibroma or neurilemmoma. This case merits attention because extensive dystrophic tumoral calcification in the lobules prompted an initial misdiagnosis of foreign body granuloma.
Calcification in neurothekeoma has not previously been described.
CELLULAR Higher cellularity than myxoid type with larger spindled or epithelioid cells with vesicular nuclei
- Am J Surg Pathol. 2007 Mar;31(3):329-340 Abstract quote
Cellular neurothekeomas are distinctive benign cutaneous tumors of uncertain histogenesis. As relatively few cases have been reported, their clinical features and morphologic spectrum remain incompletely defined, and the significance of atypical histologic features is uncertain.
This study examined the clinicopathologic and immunohistochemical features of 133 cellular neurothekeomas received between 1987 and 2003. There was a 1.8:1 female predominance, with a mean age of 25 years (84% <40 y). Mean tumor size was 1.1 cm (range: 0.3 to 6 cm; 90% <2 cm). The tumors arose most often on the upper limb (35%) or head and neck (33%). Fifty-two percent of the tumors were limited to the dermis, and 48% also involved superficial subcutaneous tissue. In 30% of cases, neurothekeoma was suggested by the referring pathologist; the most common other diagnoses offered were plexiform fibrohistiocytic tumor, benign fibrous histiocytoma, and a low-grade sarcoma.
Histologically, most cases were poorly marginated; 33 (25%) infiltrated fat, and 10 (8%) entrapped skeletal muscle (all but 1 situated on the face). Nearly all tumors had a lobulated or micronodular architecture and were composed of nests and bundles of epithelioid to spindled cells with palely eosinophilic cytoplasm, often separated by dense hyaline collagen; 17 (13%) showed focally sheetlike areas, and 5 (4%) were notably plexiform. Myxoid stroma was observed in 38 (29%) tumors; 11 (8%) were predominantly myxoid. Five (4%) showed marked stromal hyalinization. Osteoclastic giant cells were seen in 20 (15%) cases. The mean mitotic rate was 3 per 10 high power fields; 28 (21%) had >/=5 per 10 high power fields. Most tumors showed mild cytologic atypia in the form of nuclear variability and small nucleoli; 33 (25%) contained notably pleomorphic cells.
All tumors were reactive for NKI-C3, 110/123 (89%) expressed neuron-specific enolase, 73/127 (57%) showed at least focal staining for smooth muscle actin, and only 1 was focally desmin positive. All tumors were negative for S-100 protein. Follow-up ranged from 5 to 146 months (mean 44 mo). Ten tumors recurred locally (7 situated on the face), after a mean of 18 months; tumor had been marginally excised or had involved excision margins in all cases with available information. No other clinical or pathologic features correlated with recurrence.
Cellular neurothekeomas have a predilection for the upper limbs and head and neck of pediatric and young adult females and rarely recur following incomplete excision. There is no good evidence that these lesions show nerve sheath differentiation and the nomenclature will likely change when the tumor cell lineage is better defined. Atypical histologic features (including pleomorphism, infiltration of subcutis, and a high mitotic rate) seem to have no clinical significance.
J Cutan Pathol. 2006 Jan;33(1):51-6. Abstract quote
Background: Cellular neurothekeoma is a relatively rare, benign cutaneous neoplasm, which usually presents as a solitary papule or nodule involving the head and neck area of young adults. Multiple neurothekeomas have not, to date, been known to occur.
Methods: We report a 30-year-old, otherwise healthy, male who presented with multiple neurothekeomas (15) in the head and neck area over a period of 12 years.
Results: While the unifying feature of all biopsied (10 of 15) lesions was the presence of epithelioid cells - the lesions differed in their cellularity and the degree of sclerosis of the stromal component. Antigenic profiling of the lesional cells revealed expression of vimentin, NKI/C3, PGP 9.5, factor XIIIa and CD68 but not S100, HMB45, MelanA, EMA, MSA, desmin, CD57 or NGF-R.
Conclusions: This case report is the first to document the occurrence of multiple cellular neurothekeomas. An unusual histologic feature of some of the biopsied lesions was the presence of a markedly sclerotic stroma.
Cellular 'neurothekeoma': an epithelioid variant of dermatofibroma?
Zelger BG, Steiner H, Kutzner H, Maier H, Zelger B.
Department of Pathology, University of Innsbruck, Austria.
Histopathology 1998 May;32(5):414-22 Abstract quote
AIMS: Cellular neurothekeoma is a rare benign cutaneous neoplasm with conflicting opinions regarding its histogenetic origin (nerve sheath, smooth muscle, myofibroblasts) as well as its relation to myxoid neurothekeoma (nerve sheath myxoma). The present series describes 15 cases whose clinicopathological features indicate a relationship to dermatofibroma.
\METHODS AND RESULTS: In this retrospective clinicopathological study, the lesions preferentially occurred in adolescents to young adults on the upper half of the body, often clinically diagnosed as some kind of fibrohistiocytic tissue response. Besides characteristic whorled nests to fascicles of palely eosinophilic epithelioid cells, all lesions showed variable clues pointing to dermatofibroma: acanthosis, ill-defined storiform periphery, peripherally accentuated prominent sclerosis and lymphocytic demarcation/infiltration. Immunohistochemically, all cases were positive with NK1C3 (CD57), KiM1p and proliferating cell nuclear antigen, seven were positive for neurone specific enolase, five for factor XIIIa, six for smooth muscle specific actin and three for E9, an antimetallothionein marker. These findings are similar to those of conventional dermatofibromas, the variability of the profile being best explained by time cycle and function dependent changes. Ultrastructurally, two cases showed microfilaments, attachment plaques, prominent pinocytosis and focal remnants of basal lamina. A careful study of the data and photomicrographs from the literature reveals that in many cases similar conclusions could be reached. Obvious discrepancies are most likely due to the confusion with myxoid neurothekeoma, a well circumscribed, more spindly and myxoid, S100 positive lesion of Schwannian origin.
CONCLUSION: The appearance of dermatofibromas is markedly influenced by architectural, e.g. in deep penetrating dermatofibroma, and/or cellular/stromal criteria, e.g. in epithelioid cell histiocytoma or sclerosing dermatofibroma. Cellular neurothekeoma seems to be a variant of dermatofibromas with both architectural and cellular/stromal peculiarities, i.e. plexiform pattern, epithelioid cytology and stromal sclerosis
Desmoplastic cellular neurothekeoma: Clinicopathological analysis of twelve cases.
Zedek DC, White WL, McCalmont TH.
Depts. of Pathology and Dermatology, University of California, San Francisco, 94115, USA.
J Cutan Pathol. 2009 Nov;36(11):1185-90. Abstract quote
BACKGROUND: Cellular neurothekeoma is a benign lesion most commonly found on the face and upper extremities in the first two decades of life.
METHODS: Retrospective clinicopathologic review of 12 examples of cellular neurothekeoma typified by prominent stromal sclerosis, a distinctive variant that we refer to as desmoplastic cellular neurothekeoma.
RESULTS: The mean age was 30 years (range, 3-55 years, 3 males, 9 females). The site was the head and neck in 3 cases, upper extremity in 4, lower extremity in 2, and trunk/abdomen in 3. All cases showed fascicles of slightly spindled and polygonal cells arrayed haphazardly in a prominent sclerotic background in the dermis and superficial subcutis. The cells displayed pale cytoplasm with indistinct membranes and vesicular nuclei with a single nucleolus. Lesional cells expressed NKI/C3, laminin, CD68, and CD10 and lacked expression of S-100 protein, EMA, and CD34. Clinical follow up was available on 10 cases with a mean duration of 24 months (range, 11-42 months) with no local recurrences or metastases.
CONCLUSIONS: The immunohistochemical staining pattern, clinical findings, and benign nature are similar to "conventional" cellular neurothekeomas. The differential diagnosis includes desmoplastic melanocytic lesions, desmoplastic spindle cell carcinoma, dermatofibroma, "immature" scar, plexiform fibrohistiocytic tumor, perineurioma, and piloleiomyoma.
- Cellular neurothekeoma with histiocytic differentiation.
Misago N, Satoh T, Narisawa Y.
Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
J Cutan Pathol. 2004 Sep;31(8):568-72. Abstract quote
Background: It is generally accepted that the two types of neurothekeoma (myxoid type and cellular type) represent the two poles of a spectrum. This concept, however, has recently been challenged, and cellular neurothekeomas have been suggested as a separate classification and are included in the 'fibrohistiocytic' category by some authors. Cellular neurothekeomas have been reported to show negative immunohistochemical staining for histiocytic markers, and PG-M1 is now considered to be the most reliable histiocytic marker.
Case report: We report a case of cellular neurothekeoma. The histopathological features in this case were typical for cellular neurothekeoma. Immunohistochemically, the neoplastic cells were diffusely positive for S-100A6 protein, PGP9.5, CD10, CD68 (KP1), PG-M1, and Vimentin, and negative for other antibodies including S-100 protein and factor XIIIa.
Conclusions: Cellular neurothekeoma expressing both KP-1 and PG-M1 is considered to show histiocytic differentiation, and may be interpreted as a neoplasm with immature nerve sheath differentiation, incidentally expressing histiocytic markers, or as an undifferentiated neoplasm derived from the neural crest cells of nerve sheath/fibrohistiocyte lineage. These results, such as the concomitant expressions of PGP9.5/S-100A6 and PG-M1/CD68 (KP-1), support the theory of multiple differentiation in cellular neurothekeomas. The significance of the expression of CD10 in this cellular neurothekeoma is unclear.
Unusually differentiating immature nerve sheath myxoma in association with dermal melanocytosis.
Misago N, Narisawa Y, Inoue T, Yonemitsu N.
Department of Internal Medicine, Saga Medical School, Japan.
Am J Dermatopathol 1999 Feb;21(1):55-62 Abstract quote
A 44-year-old woman presented with a slightly elevated, erythematous lesion, with partially blue-black areas. The nonpigmented area histologically showed a "dissecting" fascicular growth pattern, similar to one of the patterns seen in the cellular type of nerve sheath myxoma.
The clinically pigmented part of the lesion consisted of diffusely infiltrating, broad and poorly delineated fascicles often showing nerve sheath differentiation, embedded in a highly myxomatous stroma. No part of the lesion showed the plexiform pattern typical of the classic type of nerve sheath myxoma; rather, the lesion had some common features of neurofibroma, and also was characteristically associated with a considerable number of scattered dermal melanocytes. However, based on the fascicular histologic pattern showing nerve sheath differentiation within mucinous matrix, S-100 protein-negative immunophenotype, and electron microscopic features, we considered the whole lesion in the present case to be an entity within the spectrum of nerve sheath myxoma, either mixed-type nerve sheath myxoma or unusually differentiating immature nerve sheath myxoma, except for the associated dermal melanocytosis.
Because of the intimate association of the dermal melanocytes with this nerve sheath myxoma with divergent differentiation, this lesion can also be considered as a distinctive type of benign neoplasm derived from pluripotent neural crest cells.
MYXOID HYPOCELLULAR Small cytologically bland cells arranged in a loose cellular network or in loose highly myxomatous nodules delineated by dense collagen PLEXIFORM
- Cellular neurothekeoma with a plexiform morphology: a case report with a discussion of the plexiform lesions of the skin.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Princess Margaret Hospital, University health network, Toronto, Ontario, Canada.
- J Cutan Pathol. 2007 Mar;34(3):264-9. Abstract quote
Neurothekeoma is a rare benign dermal lesion that is commonly seen in children and teenagers. Despite its name, the true nature of this lesion is uncertain and controversial, particularly after the emergence of the cellular (spindle/epithelioid) variant.
We describe the histological and immunohistochemical findings of a right thigh skin lesion in an 11-year-old girl. It consists of a dermal ill-defined plexiform mass composed of nests and fascicles of spindle cells with pale eosinophilic cytoplasm that lie within a sclerotic stroma.
The immunohistochemistry shows diffuse reactivity to CD68, matrix metalloproteinase-II, CD10 and PGP9.5 with focal reactivity to CD57 and CD34. The lesion is negative for S100, factor XIIIa, smooth muscle markers and melanocytic markers. The features are compatible with a cellular variant of neurothekeoma with plexiform pattern that also exhibits an unusual pattern of fibrohistiocytic phenotype.
Although such a lesion is benign, it has a wide but important differential diagnoses that are reviewed briefly together with a brief discussion about the origin of this rare entity.
CHARACTERIZATION Special stains Immunoperoxidase Cellular tumors
Positive for collagen IV, calponin, SMA
Negative for nerve growth factor, GFAP, CD34 and 1/11 positive for S100
Positive for S100, nerve growth factor, GFAP, CD57
Pericellular collagen IV, CD34, EMA
Less common calponin and SMA
Microphthalmia transcription factor and NKI/C3 expression in cellular neurothekeoma.
Page RN, King R, Mihm MC Jr, Googe PB.
Knoxville Dermatopathology Laboratory, University of Tennessee, Knoxville, TN 37919, USA.
Mod Pathol. 2004 Feb;17(2):230-4 Abstract quote.
While the usual or myxoid-type neurothekeoma has been reasonably well established as being a tumor of neural origin, the cellular neurothekeoma remains in disputed histogenesis.
We studied a series of 11 cellular neurothekeomas using paraffin immunoperoxidase staining with microphthalmia transcription factor (Mitf), NKI/C3, and S-100. The majority of the tumors in our series stained with NKI/C3 (9/11) and Mitf (9/11). All failed to stain with S-100. Furthermore, we divided our series of cellular neurothekeomas according to cytomorphology; tumors demonstrating predominantly spindled morphology, predominantly epithelioid morphology, and mixed spindle and epithelioid morphology. The two tumors that failed to stain with NKI/C3 both demonstrated predominantly spindled morphology.
One of the tumors that failed to stain with Mitf showed exclusive spindled morphology, while the other showed mixed morphology (spindle and epithelioid). Two of the tumors, which stained strongly with Mitf, however, showed exclusive epithelioid morphology.
This current study furthers the concept that cellular neurothekeoma is a tumor of neuroectodermal origin, and further suggests that it may express some component of melanocytic differentiation.
Cellular 'neurothekeoma': an epithelioid variant of pilar leiomyoma? Morphological and immunohistochemical analysis of a series.
Calonje E, Wilson-Jones E, Smith NP, Fletcher CD.
Department of Histopathology, St Thomas's Hospital (UMDS), London, UK.
Histopathology 1992 May;20(5):397-404 Abstract quote
Cellular neurothekeoma is a recently recognized benign cutaneous neoplasm, which is currently regarded as being of nerve sheath origin and is thought to represent a variant of conventional neurothekeoma (dermal nerve sheath myxoma).
Nine new cases presenting predominantly in adolescents or young adults are described. Morphologically they were characterized by short fascicles or small nests of palely eosinophilic epithelioid or spindle-shaped cells which ramified in an ill-defined manner between dermal collagen bundles. Myxoid matrix was absent or sparse. Scattered normal mitoses and multinucleate giant cells were often present. Immunohistochemically all nine cases were strongly NK1/C3 positive, seven were weakly NSE positive and three were smooth muscle actin positive. Staining for S-100 protein, PGP 9.5, epithelial membrane antigen and desmin was negative in all cases.
In view of its distinctive architecture and immunophenotype, both of which are totally different from conventional neurothekeoma, it is proposed that cellular 'neurothekeoma' is a separate discrete entity which may represent an epithelioid variant of pilar leiomyoma.
Cellular neurothekeoma with possible neuroendocrine differentiation.
Chang SE, Lee TJ, Ro JY, Choi JH, Sung KJ, Moon KC, Koh JK.
Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
J Dermatol 1999 Jun;26(6):363-7 Abstract quote
We report a case of cellular neurothekeoma showing unusual immunohistochemical findings and occurring on the left upper arm of a healthy 48-year-old woman. She presented with a 1 cm, red, asymptomatic, dermal nodule of 1 year duration.
A biopsy showed dermal proliferation of plexiform fascicles of spindle-shaped or polygonal cells with plentiful eosinophilic cytoplasms. The immunohistochemical profile included negative stains for S-100, CD34, factor XIIIa, CD68, HMB45, cytokeratins, and EMA, strongly positive stains for neuron specific enolase (NSE), synaptophysin, and chromogranin A, and focally positive ones for NKI/C3 and alpha-smooth muscle actin. Ultrastructural analysis showed undifferentiated mesenchymal cells with cytoplasmic projections and abundant RER.
Although we couldn't find any confirmative cell type in this cellular tumor, we believe that cellular neurothekeoma is predominantly composed of undifferentiated cells that can exhibit features of neuroendocrine cells in addition to fibroblastic or myofibroblastic ones, suggesting a divergent cell origin.
The "neurothekeoma": immunohistochemical analysis distinguishes the true nerve sheath myxoma from its mimics.
Laskin WB, Fetsch JF, Miettinen M.
Department of Pathology, Northwestern University Medical School, Chicago, IL, USA.
Hum Pathol 2000 Oct;31(10):1230-41 Abstract quote
In contrast with the myxoid variant of neurothekeoma (nerve sheath myxoma), evidence of neurosustentacular (NS) differentiation in the so-called cellular and mixed (intermediate) variants of neurothekeoma remains controversial.
In this study, we selected 22 tumors coded as neurothekeoma or nerve sheath myxoma from the Soft Tissue Registry of the AFIP. Each tumor was histologically subtyped as either a myxoid/hypocellular neurothekeoma (MN) (N = 11) or as a "cellular" or "mixed" (intermediate) neurothekeoma variant (C&MV) (n = 11) and analyzed immunohistochemically.
The MNs were composed of small, cytologically bland cells arranged in a loose cellular network or in files within highly myxomatous nodules delineated by dense collagen. The tumors showed clear-cut evidence of NS differentiation by exhibiting consistent immunoreactivity for S-100 protein (11 of 11 cases) and low-affinity nerve growth factor receptor, p75(NGFR), (NGFR) (10 of 10), and variable reactivity for glial fibrillary acidic protein (GFAP) (10 of 11) and CD57 (Leu-7) (5 of 9). They also showed pericellular collagen type IV (CIV) expression (9 of 9), scattered intralesional CD34-positive spindled cells (10 of 10), epithelial membrane antigen (EMA)-positive spindled cells located within the adjacent dense collagen (8 of 11), and immunoreactivity for alpha-smooth muscle actin (SMA) (3 of 10) and calponin (4 of 9). In 4 cases, scattered intralesional neuraxons were detected by the Bodian histochemical method or immunohistochemically with anti-neurofilament protein.
The tumors had a male-to-female ratio of 6:5, a peak incidence in the 4th decade of life, and an anatomic distribution that included the upper and lower limbs and back. The C&MVs included 9 "mixed" and 2 "cellular" variants. C&MVs differed histologically from MNs by their higher cellularity and presence of larger spindled or epithelioid cells with vesicular nuclei. Immunohistochemically, the tumor cells expressed CIV (9 of 10), calponin (7 of 9), SMA (5 of 10), Leu-7 (1 of 7), S-100 protein (1 of 11), but not NGFR, GFAP, or CD34. EMA-positive spindled cells surrounded tumor fascicles in 1 case. Intralesional neuraxons were not identified. Clinically, these tumors differed from the MNs by exhibiting a male-to-female ratio of 4:7, a peak incidence in the 2nd decade, and an upper body distribution.
Our results indicate that the MN shows NS differentiation and is the bona fide nerve sheath tumor, whereas the C&MVs fail to show convincing evidence of NS differentiation and probably warrant a separate classification.
PGP9.5: a marker for cellular neurothekeoma.
Wang AR, May D, Bourne P, Scott G.
Department of Pathology, University of Rochester Medical Center, NY 14640, USA.
Am J Surg Pathol 1999 Nov;23(11):1401-7 Abstract quote
Neurothekeomas are benign, predominantly cutaneous neoplasms that are divided histologically into myxoid, intermediate, and cellular types. Although it is generally agreed that the myxoid type of neurothekeoma has a neural origin, the lack of consistent immunoreactivity to neural markers and insufficient ultrastructural evidence of neural differentiation in cellular neurothekeoma have brought the origin of cellular neurothekeoma into question.
In this report the authors show that immunoreactivity to protein gene product 9.5 (PGP9.5)--a broad neural marker--is positive in 100% of cases of cellular neurothekeoma using microwave antigen retrieval, as well as in all cases of myxoid and intermediate neurothekeoma. In contrast, immunoreactivity to S-100 protein is only positive in 3 of 12 cases of cellular neurothekeoma. These results show that PGP9.5 is a useful marker for identifying cellular neurothekeoma, as well as other types of neurothekeomas using the antigen retrieval method.
The results are consistent with the notion that cellular neurothekeoma has a neural differentiation.
Neurothekeoma of Gallager and Helwig (dermal nerve sheath myxoma variant): report of a case with electron microscopic and immunohistochemical studies.
Aronson PJ, Fretzin DF, Potter BS.
J Cutan Pathol 1985 Dec;12(6):506-19 Abstract quote
A patient presented with a frontal nodule of the scalp. Histopathological examination revealed a myxomatous multilobulate tumor composed of epithelioid cells with variable pleomorphism. Perineurium-like structures were seen but only around isolated lobules located at the tumor periphery. Electron microscopy revealed polygonal cells and cells with elongated cytoplasmic processes. Many cells had myelinoid figures. A basement membrane-like lamina was noted around some cells. Some of the tumor cells were immunoreactive for myelin basic protein. This finding suggests that the tumor cells are of schwannian type.
Neurothekeoma of Gallager and Helwig is a rare, probably benign tumor with fairly distinctive histopathologic characteristics. It appears to be a variant of dermal nerve-sheath myxoma.
Neurothekeoma. Report of a case with immunohistochemical and ultrastructural studies.
Henmi A, Sato H, Wataya T, Inaniwa Y, Mori Y.
Acta Pathol Jpn 1986 Dec;36(12):1911-9 Abstract quote
A case of neurothekeoma in a 52-year-old woman is reported. The tumor developed on the medial aspect of the right nostril as a well-demarcated, dome-shaped, erythematous nodule of rubbery consistency. Microscopically, it consisted of numerous nests and cords of spindle-shaped cells in the dermis. Some of the tumor cell nests appeared epithelial-like, while the other areas showed a myxomatous appearence with various amount of mucinous matrix in the intercellular space. Neurothekeoma is a benign cutaneous tumor, and is considered to be of schwann cell origin. In the present case, the tumor cells did not stain positively for S-100 protein, despite the light microscopic suggestion of peripheral nerve origin. Ultrastructurally, most tumor cells contained a large number of myelinoid figures. This ultrastructural finding appears to be a useful diagnostic characteristics of neurothekeomas.
Ultrastructural spectrum of cutaneous nerve sheath myxoma/cellular neurothekeoma.
Argenyi ZB, Kutzner H, Seaba MM.
Department of Pathology, University of Iowa Hospitals & Clinics, Iowa City 52242-1009, USA.
J Cutan Pathol 1995 Apr;22(2):137-45 Abstract quote
The histogenesis of cutaneous nerve sheath myxoma (NSM)/cellular neurothekeoma (CNT) is still controversial.
In this study, we examined the ultrastructural features of 16 NSM (3 classical, 11 CNT, and 2 mixed NSM/CNT). We classified the cells into 4 groups ultrastructurally. Type I cells were undifferentiated polygonal cells with ovoid nuclei, cytoplasmic microfilaments, and occassionally with microfilament-associated dense bodies. In most cells, the cytoplasmic membrane showed focal membranous densities and occasional basal-lamina-like material. This cell type comprised approximately 90% of CNT. Type II cells were more differentiated, had ovoid or spindled shapes, were rich in intracytoplasmic filaments, and were surrounded by continuous basal lamina. These cells were consistent with Schwann cells and were present in the classical and mixed forms of NSM, and in a single case of CNT. Type III cells had features of perineurial cells and were relatively rare in classical NSM. Type IV cells resembled fibroblasts and were encountered in all variants of NSM.
These results support the view that 1) the classical NSM has neural (mainly Schwann cell) differentiation, 2) CNT is predominantly composed of undifferentiated cells with partial features of Schwann cells, smooth muscle cells, myofibroblasts and fibroblasts, suggesting a divergent differentiation, and 3) CNT and NSM represent a histologic spectrum, but in CNT, the neural features are not fully expressed.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES MELANOMA Histologic spectrum of neurothekeoma and the value of immunoperoxidase staining for S-100 protein in distinguishing it from melanoma.
Husain S, Silvers DN, Halperin AJ, McNutt NS.
Department of Pathology, College of Physicians and Surgeons, Columbia-Presbyterian Medical Center, New York, New York.
Am J Dermatopathol 1994 Oct;16(5):496-503 Abstract quote
Neurothekeoma, a benign cutaneous lesion of probable nerve sheath origin, is divided histologically into two subtypes--myxoid and cellular. However, we believe that neurothekeoma encompasses a wider spectrum of lesions, with the myxoid and cellular subtypes falling at either end of the morphologic spectrum. Because the cellular variant of neurothekeoma sometimes resembles melanoma, it presents a difficult diagnostic problem.
We report the histologic and immunohistochemical findings in 14 cases of neurothekeoma and review the findings in 35 additional cases from the literature. A detailed analysis of the histologic spectrum is also included. When examined by immunostains, only the myxoid variants of neurothekeoma stain positively for S-100 protein.
We conclude that when the histological differential diagnosis is between cellular neurothekeoma and melanoma, an S-100-positive lesion should be regarded as melanoma.
NERVE SHEATH MYXOMA
- Nerve Sheath Myxoma: A Clinicopathologic and Immunohistochemical Analysis of 57 Morphologically Distinctive, S-100 Protein- and GFAP-Positive, Myxoid Peripheral Nerve Sheath Tumors With a Predilection for the Extremities and a High Local Recurrence Rate.
Fetsch JF, Laskin WB, Miettinen M.
From the *Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC; and the daggerDepartment of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Am J Surg Pathol. 2005 Dec;29(12):1615-1624. Abstract quote
This report describes the clinicopathologic findings in 57 cases of nerve sheath myxoma.
Our study group included 34 males and 23 females, ranging from 8 to 72 years of age at the time of their first surgical procedure (mean, 36 years; median, 34 years). The patients typically presented with solitary, superficial, multinodular masses in the 0.5- to 2.5-cm size range.
Eighty-six percent of cases occurred in the extremities, with the most common locations being the hand/fingers (n = 22), knee/pretibial region (n = 10), and ankle/foot (n = 7). Only 7 cases (12.3%) involved the trunk or head and neck region. The tumors were generally slow growing, and often, they were present for many years before surgical resection was sought. In the majority of instances, the lesions were painless.
Histologically, the tumors involved the dermis and/or subcutis, and they formed distinct multinodular/multilobular masses with abundant myxoid matrix and a peripheral fibrous border. All cases had small epithelioid Schwann cells in corded, nested, and/or syncytial-like aggregates, a variable number of Schwann cells with a ring-like appearance, and scattered spindled and stellate-shaped Schwann cells. These cells often had cytoplasmic-nuclear invaginations, and they were immunoreactive for S-100 protein, glial fibrillary acidic protein, neuron specific enolase, and CD57. They were also bordered by collagen IV. Epithelial membrane antigen-positive perineurial cells were typically present in small numbers, primarily in the fibrous tissue directly adjacent to the myxoid nodules. CD34-positive intraneural fibroblasts were generally sparse. Mitotic figures were uncommon. All cases were initially managed by simple excision, and in almost all instances, tumor extended to the tissue edge. Follow-up information is available for 34 patients (follow-up range, 8 months to 28 years; median follow-up interval, 14 years 3 months). Sixteen patients (47%) had one (n = 11) or more (n = 5) local recurrence of their tumor, and 2 additional patients had findings suspicious for a recurrence.
Nerve sheath myxomas are morphologically distinct peripheral nerve sheath tumors with a peak incidence in the fourth decade of life and a strong predilection for the extremities. These tumors have a relatively high local recurrence rate when managed by simple local excision. They appear to be unrelated to so-called cellular and mixed-type neurothekeomas.
Perineuroma. A frequently unrecognized entity with emphasis on a plexiform variant.
Zelger B, Weinlich G, Zelger B.
Department of Pathology, University of Innsbruck, Austria.
Adv Clin Path 2000 Jan;4(1):25-33 Abstract quote
AIMS: The present series describes six cases of perineurioma, a rare and frequently unrecognized entity, including one case with an unusual plexiform growth pattern.
METHODS: Retrospective clinicopathologic study of six perineuriomas.
RESULTS: All lesions occurred on the upper extremities or shoulders of adults, five in females. Histologically, all six cases of perineurioma had been initially unrecognized or misdiagnosed as dermatofibroma, fibroma of tendon sheath, neurofibroma, schwannoma, or naevus, respectively. Scanning magnification revealed well circumscribed, dermal to subcutaneous lesions without capsule formation. Besides characteristic onion bulbs", i.e. concentric whorls of epithelioid to spindle-shaped cells, there was great variation of histomorphologic features: single nodules or plexiform architecture; a few to many concentric whorls; five to several dozens of cell layers in concentric whorls; high to low cellularity; round/oval to spindle-shaped/wavy cells/nuclei; delicate to prominent collagen; variable mucin, sclerosis, and/or intralesional clefts. Immunohistochemically, all lesions were consistently positive for EMA, ultrastructurally (1 case) with evidence of perineurial differentiation such as slender and elongated, bipolar cytoplasmic processes with discontinuous basal lamina, prominent pinocytosis and desmosome-like junctions.
CONCLUSION: Our series documents that cutaneous and subcutaneous perineurioma is frequently unrecognized or misinterpreted and may occasionally show a plexiform growth pattern. The differential diagnosis of plexiform variants includes a variety of plexiform lesions such as naevi, neurofibroma, schwannoma, etc. Historically, similar plexiform lesions seem to have been published as nerve sheath myxoma/neurothekeoma, Pacinian neurofibroma or perineurial myxoma. This terminology is imprecise and confusing and, thus, should be avoided in favour of the correct term of perineurioma.
SPITZ NEVUS, PLEXIFORM
Plexiform spitz nevus: an intradermal spitz nevus with plexiform growth pattern.
Spatz A, Peterse S, Fletcher CD, Barnhill RL.
Department of Pathology, Institut Gustave-Roussy, Villejuif, France.
Am J Dermatopathol 1999 Dec;21(6):542-6 Abstract quote
Two cases of a distinctive variant of Spitz (spindle and epithelioid cell) nevus are described. One lesion developed on the lower leg of a 17-year-old boy and the other lesion on the back of a 52-year-old man.
The microscopic appearance was characterized by a plexiform arrangement of bundles and lobules of enlarged spindle to epithelioid melanocytes throughout the superficial and deep dermis. Intraepidermal melanocytic proliferation was unappreciated. Some lobules were circumscribed by a thin rim of compressed fibrous tissue. In both cases a myxoid stroma was present. The cells had abundant eosinophilic cytoplasm with well-defined borders. The nuclei were enlarged, consistently ovoid and vesicular, with small nucleoli. Both cases contained scattered multinucleate giant cells similar to those observed in classical form of Spitz nevi. No melanin pigment was detectable by light microscopy. No mitoses were observed in one case and a rare mitosis was present in the other.
Tumor cells were strongly immunoreactive for S-100, but not for HMB-45, desmin, and actin. The differential diagnosis of this distinctive tumor includes desmoplastic/neurotropic melanoma, plexiform spindle cell nevus, cellular blue nevus, plexiform neurofibroma, and cellular neurothekeoma. The designation of "plexiform Spitz nevus" is chosen to emphasize its distinctive plexiform growth pattern.
PROGNOSIS AND TREATMENT CHARACTERIZATION TREATMENT Complete excision
Hum Pathol 2000;31:1230-1241
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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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