Improved discrimination of melanotic schwannoma from melanocytic lesions by combined morphological and GNAQ mutational analysis

Abstract

The histological differential diagnosis between melanotic schwannoma, primary leptomeningeal melanocytic lesions and cellular blue nevus can be challenging. Correct diagnosis of melanotic schwannoma is important to select patients who need clinical evaluation for possible association with Carney complex. Recently, we described the presence of activating codon 209 mutations in the GNAQ gene in primary leptomeningeal melanocytic lesions. Identical codon 209 mutations have been described in blue nevi. The aims of the present study were to (1) perform a histological review of a series of lesions (initially) diagnosed as melanotic schwannoma and analyze them for GNAQ mutations, and (2) test the diagnostic value of GNAQ mutational analysis in the differential diagnosis with leptomeningeal melanocytic lesions. We retrieved 25 cases that were initially diagnosed as melanotic schwannoma. All cases were reviewed using established criteria and analyzed for GNAQ codon 209 mutations. After review, nine cases were classified as melanotic schwannoma. GNAQ mutations were absent in these nine cases. The remaining cases were reclassified as conventional schwannoma (n = 9), melanocytoma (n = 4), blue nevus (n = 1) and lesions that could not be classified with certainty as melanotic schwannoma or melanocytoma (n = 2). GNAQ codon 209 mutations were present in 3/4 melanocytomas and the blue nevus. Including results from our previous study in leptomeningeal melanocytic lesions, GNAQ mutations were highly specific (100%) for leptomeningeal melanocytic lesions compared to melanotic schwannoma (sensitivity 43%). We conclude that a detailed analysis of morphology combined with GNAQ mutational analysis can aid in the differential diagnosis of melanotic schwannoma with leptomeningeal melanocytic lesions.

Fig. 1

Melanotic schwannoma (case 4) showing a circumscribed tumor, covered by a fibrous capsule and containing several psammoma bodies (a) (×50). Detail of the same lesion showing spindle cell morphology, an ample amount of melanin pigment and a psammoma body (case 4) (b) (×200). Melanotic schwannoma (case 8) with more epithelioid cell morphology, nuclear pseudoinclusions (arrow) and large vacuoles resembling fat (c) (×400). Strong and diffuse positivity for, respectively, S-100 and HMB-45 in a melanotic schwannoma (case 4) (d, e) (×25, ×100). Same lesion with pericellular deposition of basement membrane material (case 4) (f) (Laguesse stain, ×400)

Fig. 2

Intermediate-grade melanocytoma (case 20) with invasion of neuroglial tissue; note the Rosenthal fibers (arrow) in the surrounding neuropil (a) (×200). Epithelioid cell morphology with bland nuclei and small nucleoli in a melanocytoma (case 22) (b) (×400). Focal positivity for S-100 in the same lesion (case 22) (c) (×200). Diffuse positivity for HMB-45 and Melan-A, respectively, in the same lesion (d, e) and a nested staining pattern in the reticulin stain (f) (case 22) (Laguesse stain, ×200)

Fig. 3

Case 24 was a variably, partly heavily pigmented lesion consisting of spindle to pleomorphic cells (a, c) (×200), showing infiltrative growth in a ganglion at the lumbar spinal region with dispersed incorporated ganglion cells (arrow) (b) (×400). The nuclei showed marked atypia with conspicuous nucleoli (c) (×200). In the reticulin stain, both a pericellular (d) and nested staining pattern were seen (e) (Laguesse, ×100). We, therefore, favored the diagnosis of a melanotic schwannoma with atypical features suggestive of aggressive behavior. Molecular analysis of this case did not reveal mutations in the GNAQ gene