Clear cell change has been demonstrated in many cutaneous entities; however, there have been only two reports of clear cell neurofibroma. We present the third case of this unusual subtype. A 25-year-old female presented clinically with a picture of neurofibromatosis Type 1 including multiple cutaneous nodules. Biopsy from one of these nodules revealed a normal epidermal covering and a dermal benign neoplastic growth formed of a mixture of spindle cells and clear cells showing vacuolated cytoplasm. The neoplastic cells showed round nuclei with prominent nucleoli. Immunohistochemical staining showed positivity to S-100 and CD68 with negative expression of calretinin, CK, Melan-A, HMB-45, CD34, and smooth muscle actin. Clear cell neurofibroma should be considered in dealing with clear cell cutaneous lesions, giving attention to characteristic clinical, histopathological, and immunohistochemical features. CD68 could be expressed in neurofibroma, and this should not be misinterpreted as a histiocytic lesion.
Keywords: CD68, clear cell change, cutaneous neoplasm, neurofibroma
|How to cite this URL:|
Aboelnasr LS, Dawoud MM, Mahmoud SF, Abdou AG. Clear cell neurofibroma: A rare and confusing variant. J Microsc Ultrastruct [Epub ahead of print] [cited 2022 Nov 30]. Available from: https://www.jmau.org/preprintarticle.asp?id=361121
| Introduction|| |
Clear cell change has been shown in many cutaneous entities. Cutaneous neurofibromas are benign dermal tumors formed of fascicles of spindle-shaped cells with scanty cytoplasm and wavy nuclei in a myxoid stroma showing many blood vessels. Several histopathological variants of neurofibroma are recognized including classic, cellular, myxoid, hyalinized, epithelioid, plexiform, and others.,,, Clear cell neurofibroma has also been called balloon cell neurofibroma and has been reported twice in the literature., In this report, we present the third case of this unusual subtype.
| Case Report|| |
A 25-year-old female presented with multiple cutaneous swellings, café au lait patches, and optic glioma, a picture suggestive of neurofibromatosis Type 1. A biopsy measuring 2 cm × 2 cm from one of these cutaneous swellings revealed a normal epidermal covering and a dermal benign neoplastic growth formed of spindle-shaped cells, most of them showing clear cell change in the form of vacuolated cytoplasm. The neoplastic cells showed round nuclei with occasional prominent nucleoli [Figure 1]a, [Figure 1]b, [Figure 1]c.
|Figure 1: Histopathological features of clear cell neurofibroma: Population of spindle cells together with clear cells, (a: H and E, ×40). Spindle cells showed wavy nuclei admixed with clear cells with vacuolated cytoplasm, (b: H and E, ×100). Spindle and clear cells have round-to-ovoid nuclei and occasional prominent nucleoli, (c: H and E, ×400). The clear cells were negative for PAS (d: PAS ×100). PAS: Periodic acid–Schiff|
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Immunohistochemical staining showed positivity to S-100 and CD68. The tumor cells were negative for calretinin, cytokeratin, Melan-A, and HMB-45 [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. The cells were also negative for periodic acid–Schiff (PAS) [Figure 1d]. The study was approved by the ethical committee of the Faculty of Medicine, Menoufia University (Derma 19/21).
|Figure 2: Strong S-100 positivity highlights both spindle and clear cells, (a: ×100). Strong diffuse CD68 positivity was noted in the clear cells, (b: ×100). Negativity was evident in calretinin (c: ×100) and HMB-45, (d: ×100)|
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| Discussion|| |
Several cutaneous neoplasms with a wide variety of differentiation, including epithelial, mesenchymal, fibrohistiocytic, and melanocytic could show clear cell morphology.
The clear cell variant of neurofibroma has only been reported twice in the literature. The clear cell change was suggested to be a degenerative process., The first reported case was slightly different from ours, being in an older male with a papule on the right clavicle. The authors described a tumor composed of superficially located cells with a vacuolated cytoplasm that coexisted with a deeper proliferation of spindle-shaped cells. Our case is much like the second reported case, being in a middle-aged female with a cutaneous lesion on the back. The biopsy showed clear cells intimately associated with spindle cells in a diffuse process throughout the dermis. Unlike our case, neurofibromatosis was not reported in the previous two cases.,
Interestingly, our case showed diffuse positive expression for CD68, as also reported by Wilsher, unlike the first case report that showed focal immunoreactivity for CD68. Being a Schwann cell-derived neoplasm, CD68 positivity in a neurofibroma may be related to Schwann cell heterogeneity, as stated by Moore that there is a subset of Schwann cells that can express CD68. It may refer to a histiocytic component associated with degenerative changes as reported previously in schwannoma. A further possibility is that it may be due to intracellular accumulation of phagolysosomes as suggested in a CD68 positive subset of granular cell tumors.
The diagnosis of the present case and the two previously reported cases were supported by diffuse and strong S-100 positivity together with negativity to epithelial and melanocytic markers., Owing to cytokeratin negativity in our case, both primary and metastatic epithelial neoplasms have been excluded.
Owing to calretinin negativity and the absence of the characteristic mixture of hypocellular and hypercellular patterns, schwannoma was excluded.
Cutaneous lipomatous neurofibroma has recently been reported as typical neurofibroma mixed with mature adipose tissue elements, which were absent in our case.
Clear cell change has also been reported in melanocytic neoplasms, however, in the latter, there would be a diffuse strong expression of Melan-A and HMB-45.
Clear cell histiocytic neoplasms or xanthomas are also CD68 positive, however, unlike our case, they stain negative for S-100. Cutaneous dermal neoplasms that are positive for CD68 also include dermatofibroma and clear cell fibrous papule, but the present case did not show the characteristic storiform pattern of dermatofibroma or the classic facial location of the fibrous papule. Furthermore, these entities lacked S-100 expression.,
Clear cell granular cell tumors also show both S-100 and CD68 expression with some cases showing negativity to PAS. However, unlike our case, granular cell tumors show sheets of large polygonal cells with eosinophilic, granular cytoplasm, enlarged nuclei with prominent nucleoli, and characteristic lymphoid aggregates within and at the periphery of the tumor. Furthermore, the multiplicity of cutaneous swellings and the clinical picture of neurofibromatosis are in favor of neurofibroma.
Primary cutaneous perivascular epithelioid cell tumors (PEComas) are reported to involve extremities in most cases. Unlike our case, these tumors are characterized by epithelioid cells with clear, pale eosinophilic, or granular cytoplasm arranged into nests or trabeculae that are separated by a network of delicate branching capillaries. These tumors express HMB-45 and Melan-A, but they lack S-100 expression.
Cutaneous clear cell sarcoma and dermal pleomorphic liposarcoma are malignant dermal neoplasms that can also show a clear cytoplasm and express S-100. However, unlike our case, these lesions are characterized by bizarre pleomorphic cells, multinucleated giant cells, necrosis, and increased mitotic figures., Moreover, cutaneous clear cell sarcomas show expression of Melan-A and HMB-45.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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Asmaa Gaber Abdou,
Department of Pathology, Faculty of Medicine, Menoufia University, Shebein Elkom 32511
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]