Elsevier

Pathology

Volume 49, Issue 1, January 2017, Pages 44-49
Pathology

Anatomical pathology
Protein gene product 9.5 (PGP9.5) expression in benign cutaneous mesenchymal, histiocytic, and melanocytic lesions: comparison with cellular neurothekeoma

https://doi.org/10.1016/j.pathol.2016.09.061Get rights and content

Summary

Cellular neurothekeoma (CNTK) frequently enters the differential diagnosis of a benign dermal cellular proliferation. Diagnosis often relies on immunohistochemistry including the use of protein gene product 9.5 (PGP9.5). A previous study demonstrated PGP9.5 expression across a wide variety of soft tissue neoplasms. We explored the utility of this antibody in distinguishing CNTK from other benign dermal-based lesions. A cohort of CNTK (n = 7) and benign cutaneous lesions of neural (n = 28), fibrohistiocytic (n = 23), fibroblastic (n = 25), histiocytic (n = 18), myofibroblastic (n = 7), smooth muscle (n = 14), and melanocytic (n = 12) differentiations were immunostained with PGP9.5. Staining was graded by H-score and compared with CNTK. A significantly higher H-score was found in CNTK compared with the fibrohistiocytic (p = 0.0001), histiocytic (p = 0.0016), myofibroblastic (p = 0.0003), smooth muscle (p < 0.0001), and melanocytic (p = 0.0004) groups, with the exceptions of plexiform fibrohistiocytic tumour, xanthoma, and xanthogranuloma. No significant difference was found when comparing CNTK with fibroblastic and neural lesions, with the exceptions of neurofibroma and perineurioma. In conclusion, PGP9.5 is helpful in distinguishing CNTK from most benign cutaneous fibrohistiocytic, histiocytic, myofibroblastic, smooth muscle, and melanocytic lesions. In addition to CNTK and neural lesions, PGP9.5 is also expressed in benign fibroblastic lesions, and therefore distinction of these lesions should not be based on PGP9.5 positivity.

Introduction

In dermatopathology practice, it is not uncommon to encounter biopsies of benign superficial dermal lesions which are difficult to classify based on histomorphology alone. Cellular neurothekeoma (CNTK) readily enters the differential diagnosis of these lesions owing to its nondescript clinical appearance, histomorphological heterogeneity, and potential to mimic a variety of other dermal-based lesions.1, 2 One of the immunohistochemical markers for CNTK is protein gene product 9.5 (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase with a primary function in ubiquitin regeneration following intracellular protein degradation.3 This protein is localised in normal neural and neuroendocrine tissues, as well as tumours of neuroendocrine and neuroectodermal origins. While PGP9.5 expression in CNTK seemed to support a former belief that it is a tumour of nerve sheath lineage,4 more recent studies have pointed to a non-neural, possibly fibroblastic/fibrohistiocytic origin.5, 6, 7, 8 The specificity of PGP9.5 for neural or nerve sheath differentiation was also disputed by a previous study which demonstrated PGP9.5 expression in a wide variety of deep soft tissue neoplasms, including malignant peripheral nerve sheath tumour, dermatofibrosarcoma, malignant fibrous histiocytoma, low-grade fibromyxoid sarcoma, angiosarcoma, pleomorphic liposarcoma, rhabdomyosarcoma, synovial sarcoma, and melanoma.9

While PGP9.5 is thought to be of no diagnostic value in deep soft tissue neoplasms, little data is available on PGP9.5 expression in benign dermal-based lesions other than CNTK, especially those that may potentially mimic the latter. Distinction of CNTK from other benign dermal-based lesions is important as conservative excision is often performed for CNTK to avoid local recurrence upon incomplete excision,10, 11 while no treatment is usually needed for most of its benign mimics. Due to the lack of more specific markers for CNTK described to date, PGP9.5 remains one of the frequently used antibodies in confirming a diagnosis of CNTK. Therefore, its utility in dermatopathology practice warrants better characterisation. Herein we aimed to determine the specificity of PGP9.5 by examining its expression in a wide spectrum of benign dermal mesenchymal, histiocytic, and melanocytic lesions, in order to provide useful information on the utilisation, interpretation, and potential pitfalls of this antibody.

Section snippets

Materials and methods

This study was approved by the Institutional Review Boards at University of Michigan and Massachusetts General Hospital. The surgical pathology archive at University of Michigan was searched for the following: ‘cellular neurothekeoma’, ‘schwannoma’, ‘palisaded encapsulated neuroma’, ‘granular cell tumor’, ‘neurofibroma’, ‘plexiform fibrohistiocytic tumor’, ‘fibrous papule’, ‘pleomorphic fibroma’, ‘myxoma’, ‘superficial acral fibromyxoma’, ‘trichofolliculoma’, ‘fibrofolliculoma’, ‘Rosai–Dorfman

Results

The final cohort consisted of 134 cases categorised as cellular neurothekeoma (n = 7), neural/nerve sheath lesions (n = 28), fibrohistiocytic lesions (n = 23), fibroblastic lesions (n = 25), histiocytic lesions (n = 18), myofibroblastic lesions (n = 7), smooth muscle lesions (n = 14), and melanocytic lesions (n = 12) based on their presumed lineage of differentiation. The mean H-scores and the p values from comparison with the CNTK group are summarised in Table 1. Representative examples from all examined

Discussion

Cellular neurothekeoma is a benign dermal neoplasm most commonly occurring on the head and neck and upper limbs of young adults.5, 10 Classically, CNTK forms a fairly well circumscribed dermal papule or nodule consisting of nests of bland epithelioid to spindle cells separated by collagenous bands. However, CNTK may also exhibit different growth patterns and morphological variants which may be easily confused with other dermal-based mesenchymal, histiocytic and melanocytic lesions.1, 2 To add

Acknowledgements

Presented at the 52nd Annual Meeting of the American Society of Dermatopathology, San Francisco, CA, USA, October 8–11, 2015. The authors would like to thank Tina Fields (Research Histology and Immunohistochemistry Laboratory, Comprehensive Cancer Center, University of Michigan) for her help with immunohistochemistry.

References (51)

  • A. D’Antonio et al.

    Desmoplastic cellular neurothekeoma mimicking a desmoplastic melanocytic tumor

    J Am Acad Dermatol

    (2011)
  • B. Thakral et al.

    Cellular neurothekeoma with fascicular growth features mimicking cellular dermatofibroma

    Am J Dermatopathol

    (2011)
  • A.R. Wang et al.

    PGP9.5: a marker for cellular neurothekeoma

    Am J Surg Pathol

    (1999)
  • R.L. Gallager et al.

    Neurothekeoma—a benign cutaneous tumor of neural origin

    Am J Clin Pathol

    (1980)
  • J.F. Fetsch et al.

    Neurothekeoma: an analysis of 178 tumors with detailed immunohistochemical data and long-term patient follow-up information

    Am J Surg Pathol

    (2007)
  • I. Fried et al.

    SOX-10 and MiTF expression in cellular and ‘mixed’ neurothekeoma

    J Cutan Pathol

    (2014)
  • N. Misago et al.

    Cellular neurothekeoma with histiocytic differentiation

    J Cutan Pathol

    (2004)
  • J.L. Hornick et al.

    Cellular neurothekeoma: detailed characterization in a series of 133 cases

    Am J Surg Pathol

    (2007)
  • J.F. Fetsch et al.

    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

    Am J Surg Pathol

    (2005)
  • D.R. Fullen et al.

    Antibody to S100a6 protein is a sensitive immunohistochemical marker for neurothekeoma

    J Cutan Pathol

    (2003)
  • J.A. Plaza et al.

    Immunohistochemical expressions of S100A6 in cellular neurothekeoma: clinicopathologic and immunohistochemical analysis of 31 cases

    Am J Dermatopathol

    (2009)
  • R. Sachdev et al.

    Frequent positive staining with NKI/C3 in normal and neoplastic tissues limits its usefulness in the diagnosis of cellular neurothekeoma

    Am J Clin Pathol

    (2006)
  • D.R. Fullen et al.

    S100A6 expression in fibrohistiocytic lesions

    J Cutan Pathol

    (2001)
  • M.H. Idriss et al.

    S100A6 expression in cutaneous smooth muscle neoplasms

    APMIS

    (2015)
  • M. Malhalingam et al.

    Multiple cellular neurothekeomas – a case report and review on the role of immunohistochemistry as a histologic adjunct

    J Cutan Pathol

    (2006)
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