Neurocristic Cutaneous Hamartoma With Perineuriomatous Differentiation: Can It Be Distinguished From Perineuriomatous Melanocytic Nevi?

To the Editor: During the third and fourth weeks of pregnancy, the central nervous system is developed by fusion of the ectodermal neural folds.1 This process gives rise to neural crest cells that lie between the newly formed neural tube and the overlying ectoderm. Some of these neural crest cells colonize the skin and differentiate into melanocytes.1 Other neural crest cells migrate throughout the body and differentiate into neurosustentacular elements such as the Schwann cells associated with the peripheral nerves. In the head and neck region, neural crest cells also undergo ectomesenchymal differentiation and form bone, cartilage, meninges, and vascular smooth muscle.1 Abnormal neural crest development leads to a variety of pathologies known as neurocristopathies.2 Examples include Waardenburg syndrome, Hirschsprung disease, neurofibromatosis type 1, neurocutaneous melanosis, and congenital melanocytic nevi.3 Therefore, an understanding of neural crest development elucidates the embryological link between melanocytic nevi and the cellular components of the peripheral nervous system. We report the case of a 34-year-old woman who presented with a nodule on the dorsum of her right hand, near the metacarpal joint between D2-3. The nodule was clinically suspected to be a cyst, but a biopsy was performed to rule out neoplasia. Histopathologically, the lesion revealed plexiform whorls of stellate to spindled cells throughout the reticular and papillary dermis (Fig. 1). Adnexal and neurovascular tropism were observed. These whorls demonstrated a biphasic appearance. A first cellular population consisted of stellate cells to tissue culture–like monotonous cells with ample feathery cytoplasm: a frank perineurial-like appearance. This population alternated with syncytia of ovoid-to-spindled monotonous cells with minimal cytoplasm and inconspicuous nucleoli. Both populations were interspersed with bland, dendritic, and epithelioid pigmented cells of varying sizes. A superficial and deep perivascular infiltrate was also noted.FIGURE 1.: A, Excised lesion of the left wrist (H&E ×50). B, Histopathological examination showing a biphasic growth of stellate whorls and syncytial ovoid to spindled cells. Both populations were interspersed with pigmented dendritic and epithelioid cells (H&E ×100). C, Sparse pigmented dendritic and epithelioid cells within the whorls. We also note circumferential involvement of an eccrine gland (H&E ×200). H&E, hematoxylin and eosin.The spindle cells showed avid CD34 and EMA-fingerprint cytoplasmic staining (Figs. 2A–B) and were negative for S100 and neurofilament, suggestive of perineuriomatous differentiation. Glut-1 was positive in several cells. The accompanying pigmented dendritic melanocytes were positive for S100, melan-A, and HMB45 (Figs. 2C–D), confirming nevomelanocytic differentiation. Interestingly, even melanocytes deepest in the dermis expressed HMB45, suggesting that these melanocytes were immature.FIGURE 2.: A, Diffuse immunoreactivity to CD34 in a fingerprint-like pattern characteristic of perineurioma (CD34, original magnification ×50). B, Higher power view of diffuse EMA expression in a similar fingerprint-like pattern (EMA, original magnification ×200). C, The biphasic whorls of spindle cells were negative for S100, but the sparse, pigmented, dendritic melanocytes showed avid S100 expression (S100, original magnification ×100). The absence of a diffuse staining makes schwannoma highly unlikely. D, HMB45 staining shows positive reaction for the same interspersed dendritic and epithelioid cells. In conjunction with the s100 staining pattern, we confirm the nevomelanocytic differentiation of these cells (HMB45, original magnification ×100).We diagnosed this array of nevomelanocytes and perineuriomatous spindle cells as neurocristic cutaneous hamartoma (NCH) with perineuriomatous differentiation. There was no partially circumscribed, multinodular separate growth with pleomorphism, concerning for malignant transformation of NCH.4 NCH is a rare entity characterized by a complex proliferation of nevomelanocytes, Schwann cells, and pigmented dendritic and spindled cells.5 This results in a variable histology that overlaps with the common blue nevus and congenital nevus with neural and schwannian differentiation. They usually appear as blue plaques 3–10 in size with a preponderance for the scalp.6–8 Lesions of the upper extremity have been reported similarly to our patient's case.9 Most NCH are congenital, although they may be acquired lesions, given that local neural crest cells are believed to be persistent pluripotent cells, which may at any chosen time develop a more specific differentiation.10 Interestingly, McCalmont et al have described cases of melanocytic nevi with spindled cells expressing EMA and CD34 in fingerprint-like configuration suggestive of perineurioma.3 They coined these lesions perineuriomatous melanocytic nevi and posit that this phenomenon may simply be underdiagnosed. This may lead one to question neurocristic hamartoma's status as a distinct pathological entity from a blue nevus, which in our case may have shown perineurial differentiation. Deep nevomelanocytic HMB45 expression may also be observed in the blue nevi family. However, from a molecular standpoint, DNA sequencing of NCH has not found mutations in GNAQ, BRAF, KIT, and NRAS, indicating that NCH is likely a separate entity from dermal melanocytoses or melanocytic nevi.4 Admittedly, few NCH cases have undergone molecular sequencing.4 Interestingly, the comparative genomic hybridization array profile of proliferative NCH may be similar to a proliferative melanocytic nodule with multiple entire chromosomal gains, unlike partial chromosomal copy number changes in melanoma.10,11 The behavior of malignant melanomas developing within neurocristic hamartomas may provide a clue that further distinguishes them from other melanocytic nevi such as blue nevi. Malignant melanomas in a background of neurocristic hamartoma may develop within 1–6 years in acquired lesions or within 15–67 years in congenital cases.4,5 Upon histopathology, the background of NCH features a band-like growth involving the subcutaneous fascia and a proliferation of interspersed dendritic melanocytes around adnexal and neurovascular structures. These features are not seen in malignant blue nevi, which typically arise in a setting of cellular blue nevi. From a molecular standpoint, malignant neurocristic hamartomas have lacked mutations in GNAQ, NRAS, BRAF, and KIT in both the transformed malignant counterpart and the background NCH, further distinguishing distinct conventional melanoma and other dermal melanomas. Malignant neurocristic hamartomas may also behave more favorably than melanomas arising in other congenital nevi, although they are characterized by multiple recurrences and late metastasis.4 In sum, perineuriomatous differentiation in a neurocristic hamartoma highlights the embryology of this rare neurocristopathy.

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