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Cellular neurothekeoma with neuroendocrine differentiation

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Cellular neurothekeoma with neuroendocrine differentiation
Antonio D’Antonio MD1, Roberto Cuomo MD3, Basilio Angrisani MD2, Maria Addesso MD4, Pasquale Angrisani MD1
Dermatology Online Journal 17 (4): 2

1. Unit of Pathologic Anatomy and Oncology, A.O. “San Giovanni di Dio e Ruggi d’Aragona,” via S. Leonardo, Salerno, Italy.
2. Unit of Pathologic Anatomy, University of Medicine, “University Cattolica del Sacro Cuore,” Rome, Italy
3. University of Medicine, Salerno, Italy
4. Unit of Pathologic Anatomy, Hospital Scarlato, Salerno, Italy


We report a case of cellular neurothekeoma with unusual clinicopathological features in which neuroendocrine markers, determined by immunohistochemistry were observed. Histologically, the tumor showed a micronodular architecture with hypercellular lobules composed of slightly spindled to epithelioid cells, with nuclear atypia or pleomorphism and extension into fat, skeletal muscle. Neoplastic cells were immunoreactive for NKI/C3, CD68, CD10, and smooth-muscle actin, whereas S100 and HMB-45 staining was negative. An intriguing feature was the strong expression by tumor cells of different neuroendocrine markers. Clinical follow up showed no local recurrences after five months despite the presence of positive margins. The presence of atypical histopathological features may cause diagnostic problems with malignant mesenchymal tumors, nevo-melanocytic lesions, and fibrohistiocytic tumors. The immunohistochemical profile including the positive staining for neuroendocrine markers may suggest divergent differentiation or an origin from myofibroblast and neuroendocrine cells.


Neurothekeoma (NT) is a benign skin tumor that is usually regarded as a variant of nerve sheath tumor. NTs are more common in females and younger patients and usually occur on the upper limbs, head, and neck [1, 2].

Cellular neurothekeoma (CNT) is considered a variant of classic NT, although CNTs were recently determined to be unrelated to NTs from the histogenetic point of view [3]. Histologically, classic and cellular NTs are characterized by micronodular architecture with lobules in the dermis and superficial subcutis composed of polygonal and spindle cells with or without abundant myxoid matrix [1, 3]. These cases may be difficult to diagnose because they resemble dermatofibroma, perineurioma, plexiform fibrohistiocytic tumor, or melanocytic spitzoid lesions [3, 4, 5].

We report a new case of CNT that arose in a less common location and in an older patient that was associated with an uncommon immunohistochemical staining pattern, positive for neuroendocrine markers.

Case report

A 39-year-old woman presented to our hospital with an asymptomatic, whitish-grey, keratotic papule on the left leg that had shown a slow increase in size over 10 months to 1.3 cm in diameter (Figure 1).

Figure 1Figure 2
Figure 1. A 39-year-old woman with an asymptomatic keratotic papule on the left leg

Figure 2. (a) The dermis and subcutaneous fat were filled by a multinodular array of hypercellular lobules composed of plump spindle to epithelioid cells separated by prominent fibrous septa (H&E, x10). (b) Some cells showed nuclear pleomorphism with prominent nucleoli (H&E, x40). (c) An infiltration of small lymphocytes was evident in the background of lesion (H&E, x20). (d) The tumor showed extension into fat (H&E, x20).

Histopathological examination of the epidermis showed hyperkeratosis and acanthosis, whereas the underlying dermis and subcutaneous fat were filled by a multinodular array of hypercellular lobules composed of plump spindle to epithelioid cells separated by prominent fibrous septa (Figure 2a). Some cells showed nuclear pleomorphism with prominent nucleoli (Figure 2b) and mitoses were also present. An infiltration of small lymphocytes was evident in the background (Figure 2c). The tumor showed extension into fat (Figure 2d) and skeletal muscle and involved the margins of the excision. Because of these features the tumor could be mistaken with for a malignant mesenchymal tumor or a nevo-melanocytic tumor with “spitzoid” features.

Figure 3Figure 4
Figure 3. (a) Neoplastic cells expressed NKI/C3 (immunoperoxidase, x40) (b) and CD10 (immunoperoxidase, x20).

Figure 4. (a) The immunohistochemistry showed the strong expression in the tumoral cells of different neuroendocrine markers, including synaptophysin (immunoperoxidase, x40) (b) and CD56 (immunoperoxidase, x10).

Immunohistochemical analysis showed that the epithelioid and spindle-shaped cells were positive for smooth muscle actin (Figure 3a), NKI/C3 (Figure 3b), CD68, and CD10 but were negative for CD34, EMA, and S100 protein (Dako Cytomation, Copenhagen, Denmark). An unusual immunohistochemical finding was the presence of a strong expression in the tumor cells of different neuroendocrine markers, including NSE, chromogranin A, synaptophysin (Figure 4a), and CD56 (Figure 4b), (Dako). On the basis of these findings, a diagnosis of cellular neurothekeoma with possible neuroendocrine differentiation was made. Wound healing was uncomplicated and a five-month follow-up did not show a recurrence, even though the lesion had not been re-excised.


Neurothekeoma (NT) is an unusual tumor involving the dermis that is composed of distinct lobules of bland spindle cells separated by fibrous connective tissue with an abundant myxoid matrix [1, 2]. Cellular neurothekeoma (CNT) is an uncommon variant of NT that lacks myxoid matrix and is composed of plump spindle to polygonal cells with variable nuclear atypia or pleomorphism [3]. Rarely, CNT may show a prominent sclerotic or keloid-like background, in which case it is referred to as desmoplastic CNT [5]. Typically, CNT arises as a solitary, asymptomatic papule during childhood or early adulthood. The tumors are most often found on the upper limbs, head, and neck [3, 4, 5]. Neurothekeomas are distinctive skin tumors of uncertain histogenesis and controversial nomenclature: classic NTs are regarded as a variant of nerve sheath tumors, such as neurofibromas [1, 6, 7], whereas CNTs have been recently suggested to be related to plexiform fibrohistiocytic tumors (PFHT) because of the morphologic and phenotypic similarities between these two entities [8, 9].

Beyond the different histogenesis, NTs and CNTs show different histopathological features. Both tumors have a multinodular architecture, but CNTs appear hypercellular and lack myxoid stroma. Both lesions are immunoreactive for vimentin, NKI/C3, CD10, smooth muscle actin, and CD68. They are negative for HMB45, cytokeratin, desmin, Melan A, and S100 protein [2].

Cellular neurothekeomas, like classic NTs, are benign tumors, but because of their hypercellularity, the presence of nuclear atypia, and the extension into fat or skeletal muscle, CNTs may be mistaken for a malignant tumor such as a sarcoma [3, 4]. The differential diagnoses include nevomelanocytic lesions such as Spitz tumors or desmoplastic melanoma, which in a third of cases may lack an intraepidermal or junctional component. Melanocytic lesions have to be excluded by well-known sets of classical immunomarkers [3, 4, 5, 6, 7]. Other most common differential diagnoses are plexiform fibrohistiocytic tumor, pilar leyomioma, dermatofibroma and perineurioma [3, 4, 5, 6]. Plexiform fibrohistiocytic tumor is a benign cutaneous tumor that may be confused with DCN CNT. These lesions are usually composed of myofibroblastic cells arranged in a plexiform configuration admixed with multinucleated giant cells. CNT have been recently correlated with plexiform fibrohistiocytic tumor because of the marked morphologic and phenotypic similarities between the two entities that suggested a common histogenesis [8, 9].

Some morphological features and immunohistochemical findings (CD68+, CD10+, NKI/C3+) and clinical presentations (as in our patient) may overlap with a true fibrohistiocytic tumor [10, 11]. In this case, a diagnosis of dermatofibroma should be excluded.

An interesting immunohistochemical result was the strong positive staining for neuroendocrine markers such as NSE, chromogranin, synaptophysin, and CD56, suggesting a possible neuroendocrine differentiation of the tumor cells, a feature that has been reported previously in only in one case.

Hornick and Fletcher have defined the immunohistochemical profile of a large series of CNTs [3]. In this series, all tumors were reactive for NSE in addition to the most common markers of CNT. Obvious neuroendocrine differentiation has been reported in only one case [12]. In this report, the authors suggested a possible divergent origin for NT from undifferentiated mesenchymal cells, based on the immunohistochemical and ultrastructural analysis [12]. Our results agree with this hypothesis.

We think that cellular neurothekeomas are part of a heterogeneous spectrum of lesions, including the plexiform fibrohistiocytic tumor, dermatofibroma, and other fibrohistiocytic tumors arising from a common undifferentiated mesenchymal precursor capable of divergent phenotypic expression in the direction of fibroblastic, myofibroblastic, or neuroendocrine differentiation. The frequent co-expression of alpha-smooth muscle actin, CD68, and NKI/C3, with the variable presence of neuroendocrine markers seems to confirm this hypothesis, although more cases should be evaluated.

Finally, CNT is a benign tumor even when nuclear atypia is present; only a few tumors have recurred locally and these cases had been marginally excised or had involved excision margins. Epithelioid morphology associated with an unusual clinical presentation may make the diagnosis more difficult. But taking immunohistochemical data into consideration, recognition of this lesion is made easy, even in presence of atypical or desmoplastic features. Complete excision of the tumor with negative margins is curative.


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