Perineuriomas Containing Granular Cells: 2 Distinct Variants?

Abstract

To the Editor: We read Dr. Al-Daraji's1 recent report of granular perineurioma with special interest because we recently encountered a unique case of multiple hybrid granular cell tumor-perineurioma.2 Our case and Dr. Al-Daraji's case are similar (and quite unusual), both in the association of cells having granular cytoplasm with neoplasms having classic features of perineurioma, and because each patient had more than 1 histologically similar lesion. Dr. Al-Daraji's patient had a dermal and subcutaneous lesion of the trunk and also an intraneural lesion of the sciatic nerve that was discovered 3 years later, whereas our patient had multiple (>20) cutaneous nodules on all 4 extremities, present since childhood. The neoplastic granular cells in Dr. Al-Daraji's patient stained positive for epithelial membrane antigen (EMA), claudin-1, glut-1, and NKI-C3, but negative for S-100 protein, whereas the neoplastic granular cells in our patient stained positive for S-100 protein, NKI-C3, and CD 68, but negative for EMA. In each case, the neoplastic granular cells were associated and interspersed with extensive areas of histologically classic EMA-positive perineurioma. Multiple tumors in our case contained discrete areas of classic S-100-positive, CD 68-positive, EMA-negative granular cell tumor in addition to areas of hybrid granular cell tumor-perineurioma. The granular component of both Dr. Al-Daraji's lesions was focal within otherwise classic perineuriomas. We believe that our case and possibly the tumors reported by Diaz-Flores et al3 are hybrid peripheral nerve sheath tumors (PNSTs). Peripheral nerve sheath tumors may show differentiation toward any of the cell types found in the connective sheath of the peripheral nerve: Schwann cells, perineurial cells, and fibroblasts. To the best of our knowledge, the concept of hybrid PNSTs as neoplasms composed of more than 1 cell type found in normal peripheral nerve sheaths was first used by Feany et al4 in 1998 to describe a hybrid neurofibroma-schwannoma. Ultrastructural studies have shown all 3 main cell types (Schwann cell, perineurial cell, and fibroblast) in a single PNST and also so-called transitional cells with features of 2 cell types.5 Some of these transitional cells are immunoreactive with antibodies to more than 1 cell line, and Michal et al6 reported cells with both S-100 protein and EMA positivity in 3 of their hybrid schwannoma-perineuriomas. The histological and immunohistochemical features of our case and possibly of the granular perineuriomas reported by Diaz-Flores et al are consistent with hybrid PNST showing a combination of perineurial cells (EMA positive, and S-100, CD 68, and NKI-C3 negative), granular Schwannian cells/classic granular cell tumor cells (EMA negative, and S-100, CD 68, and NKI-C3 positive), and possibly fibroblasts. Perineurial cells and fibroblasts cannot always be differentiated by immunohistochemistry, and some perineuriomas may contain a mixture of perineurial cells and fibroblasts. Perineurial cells and fibroblasts are both spindled cells that can be CD 34 positive, and EMA staining in perineuriomas can be focal and weak.7 NKI-C3 and CD 68 are lysosomal markers that are organelle specific rather than lineage specific. As noted in Dr. Al-Daraji's report,1 the focal granular cell change seen in his case seems to be a nonspecific phenomenon that has been described in multiple nonneurogenic neoplasms. In contrast, the granular cells seen in our case and possibly in the 2 granular perineuriomas reported by Diaz-Flores et al seem to be classic granular cell tumor cells (S-100 positive and probably of Schwannian origin). Perineuriomas are recently recognized relative to other PNST, and hybrid PNST is also a recent concept, so it is likely that more hybrid and unusual forms of perineurioma will be recognized and reported over the coming years. Alireza Zarineh, MD* and Michael S. Rabkin, MD, PhD† *Department of Pathology and Laboratory Medicine, Allegheny General Hospital, Pittsburgh, PA; and †Rabkin Dermatopathology Laboratory, P.C., Pittsburgh, PA