Granular Cell Tumor: when should it Granular Cell Tumor: when should it be considered malignant? be considered malignant?

Immunohistochemical study of three Immunohistochemical study of three cases cases

S.A. Senatore*, G.A. Colucci*, T.G. Carlà*, F. Floccari*,S.A. Senatore*, G.A. Colucci*, T.G. Carlà*, F. Floccari*,

A.T. Pede*, E. Villani*, A. D’Amuri*° A.T. Pede*, E. Villani*, A. D’Amuri*°

* U.O.C. Anatomia Patologica Ospedale “S. Cuore di Gesù” P.O. Gallipoli ASL/LE

° Dipartimento di Patologia Umana ed Oncologia Sez. Anatomia Patologica Università degli Studi di Siena

Granular Cell Tumor (Granular Cell Tumor (GCTGCT) is a rare neoplasm which ) is a rare neoplasm which tends to occur throughout the dermis or subcutis with a tends to occur throughout the dermis or subcutis with a predilection for the head and neck regions, soft tissue and predilection for the head and neck regions, soft tissue and mucosa of the aerodigestive tracts. mucosa of the aerodigestive tracts.

Visceral involvement is less frequent.Visceral involvement is less frequent. GCT are accepted as being of neural origin from the GCT are accepted as being of neural origin from the

Schwann-cell owing to their peculiar ultrastructural Schwann-cell owing to their peculiar ultrastructural features and immunohistochemical reactivity with S100 features and immunohistochemical reactivity with S100 protein, neuron-specific enolase (protein, neuron-specific enolase (NSENSE) and myelin–) and myelin–specific protein.specific protein.

Malignant variants represent only 1% of all cases.Malignant variants represent only 1% of all cases.

INTRODUCTION

Clinical manifestations are varied. Many present as pale Clinical manifestations are varied. Many present as pale white/yellow subcutaneous circumscribed nodules with a white/yellow subcutaneous circumscribed nodules with a normal or thickened overlying skin.normal or thickened overlying skin.

The nodules can also be itchy or painful.The nodules can also be itchy or painful.

GCT may affect people of a wide age range with a peak of GCT may affect people of a wide age range with a peak of incidence in the 4incidence in the 4thth through 6 through 6thth decades of life. decades of life.

The only cure is local surgical excision of benign GCT The only cure is local surgical excision of benign GCT while en bloc excision is recommended for malignant while en bloc excision is recommended for malignant lesions which are not sensitive to radiation and lesions which are not sensitive to radiation and chemotherapy.chemotherapy.

INTRODUCTION

CASE REPORTS CASE 1CASE 1: A 39-year-old white man presented to the ORL : A 39-year-old white man presented to the ORL

Division for a dysphonia due to a small nodule of the Division for a dysphonia due to a small nodule of the larynx which was subsequently surgically treated.larynx which was subsequently surgically treated.

CASE 2CASE 2: A 50-year-old white woman underwent clinical : A 50-year-old white woman underwent clinical evaluation in the Surgical Division for the presence of a evaluation in the Surgical Division for the presence of a non-ulcerated nodule on the anterior dorsal surface of the non-ulcerated nodule on the anterior dorsal surface of the tongue which was surgically excised.tongue which was surgically excised.

CASE 3CASE 3: A 76-year-old white man presented to the : A 76-year-old white man presented to the Surgical Division for the evaluation of a nodular lesion Surgical Division for the evaluation of a nodular lesion located beneath the surface epithelium of his back. located beneath the surface epithelium of his back. Because of the suspicion of a melanoma, he was referred Because of the suspicion of a melanoma, he was referred to a surgical management.to a surgical management.

SURGICAL FEATURES

CASE 1: CASE 1: The observed specimen consisted of numerous The observed specimen consisted of numerous fragments. The estimated size of the biggest one was of fragments. The estimated size of the biggest one was of 1,3 x 0,8 cm and had a whitish appearance.1,3 x 0,8 cm and had a whitish appearance.

CASE 2CASE 2: The lesion consisted in a whitish fragment of 1,3 : The lesion consisted in a whitish fragment of 1,3 x 0,8 cm.x 0,8 cm.

CASE 3CASE 3: Grossly, the excised specimen consisted of a : Grossly, the excised specimen consisted of a yellowish lozenged-shaped cutis of 3 x 1,4 cm. The yellowish lozenged-shaped cutis of 3 x 1,4 cm. The nodular lesion had a maximum diameter of 1,2 cm. nodular lesion had a maximum diameter of 1,2 cm.

MATERIALS & METHODS Specimens were fixed in 10% buffered formalin and Specimens were fixed in 10% buffered formalin and

paraffin embedded. 5paraffin embedded. 5m serial sections were obtained and m serial sections were obtained and routinely stained with hematoxylin-eosin (routinely stained with hematoxylin-eosin (H/EH/E) and PAS ) and PAS histochemical reaction.histochemical reaction.

Immunohistochemical studies were performed for Alpha 1 Immunohistochemical studies were performed for Alpha 1 AT, CD68, Citokeratin AE1/AE3, HMB45, Ki-67, AT, CD68, Citokeratin AE1/AE3, HMB45, Ki-67, Lysozyme, NSE, S100 protein and Vimentin.Lysozyme, NSE, S100 protein and Vimentin.

S100

NSEKi-67

H/E

MICROSCOPICAL FINDINGS: CASE 1

The H/E stained section revealed a nodular neoformation The H/E stained section revealed a nodular neoformation constituted by typical granular cells showing vescicolous constituted by typical granular cells showing vescicolous nuclei with an optically empty appearance cytoplasm.nuclei with an optically empty appearance cytoplasm.

Immunohistochemical stains for S100, NSE, CD68, Immunohistochemical stains for S100, NSE, CD68, Vimentin and Vimentin and 1AT were found positive. On the contrary 1AT were found positive. On the contrary Ki-67 had a very low proliferative index (Ki-67 had a very low proliferative index (≥ 2%≥ 2%).).

A diagnosis of GCT was performed.A diagnosis of GCT was performed.

S100

NSEKi-67

MICROSCOPICAL FINDINGS: CASE 2

The histological examination revealed a subepidermical The histological examination revealed a subepidermical pseudo-nodular neoformation constituted by typical pseudo-nodular neoformation constituted by typical granular cells showing vescicolous nuclei with abundant granular cells showing vescicolous nuclei with abundant cytoplasm. Morphological atypia was also noted.cytoplasm. Morphological atypia was also noted.

Immunohistochemical stains for S100, NSE, CD68, Immunohistochemical stains for S100, NSE, CD68, Vimentin and Vimentin and 1AT were found positive. Ki-67 had a low 1AT were found positive. Ki-67 had a low proliferative index (proliferative index (≤ 5%≤ 5%).).

The O.M. diagnosis of GCT was made and later confirmed The O.M. diagnosis of GCT was made and later confirmed by TEM evaluation.by TEM evaluation.

H/E

S100

NSE Ki-67

MICROSCOPICAL FINDINGS: CASE 3

The H/E stained section demonstrated a subepidermical The H/E stained section demonstrated a subepidermical nodular cutaneous formation extended to medium derma, nodular cutaneous formation extended to medium derma, formed by atypical pleomorphic elements showing formed by atypical pleomorphic elements showing vescicolous nuclei, nucleolated with high mitotic index, an vescicolous nuclei, nucleolated with high mitotic index, an eosinophilic granular cytoplasm, sometimes microvacuolar eosinophilic granular cytoplasm, sometimes microvacuolar with an optically empty appearance.with an optically empty appearance.

Immunohistochemical stains for Vimentin, S100, NSE, Immunohistochemical stains for Vimentin, S100, NSE, 1AT, CD68 were strong and diffusely positive. Ki-67 had 1AT, CD68 were strong and diffusely positive. Ki-67 had a high proliferative index a high proliferative index (> 50%(> 50%).).

The reported morphofunctional observations gave The reported morphofunctional observations gave evidence for a malignant cutaneous tumor with evidence for a malignant cutaneous tumor with pleomorphic granular elements (pleomorphic granular elements (MGpCTMGpCT)).

DISCUSSION The neoplasms observed are of Schwann cell origin and The neoplasms observed are of Schwann cell origin and

our diagnosis is based on their histological features and our diagnosis is based on their histological features and immunohistochemical reactivity with S100 protein and immunohistochemical reactivity with S100 protein and NSE. Ki-67 can predict the clinical behaviour and, as NSE. Ki-67 can predict the clinical behaviour and, as reported in previous studies, a rare immunostaining was reported in previous studies, a rare immunostaining was found in the benign form of GCT (found in the benign form of GCT (as showed in our 1as showed in our 1stst and and 22ndnd cases cases). ).

The distinction between benign and malignant GCT is The distinction between benign and malignant GCT is controversal because of histological similarities. By controversal because of histological similarities. By convention, GCT are classified as malignant when the convention, GCT are classified as malignant when the constituent cells show cytological features of malignancy constituent cells show cytological features of malignancy or when a morphologically benign GCT metastasizes to or when a morphologically benign GCT metastasizes to regional lymph nodes or distance sites or otherwise regional lymph nodes or distance sites or otherwise causes death.causes death.

DISCUSSION The histological criteria for a malignant classification are The histological criteria for a malignant classification are

based on the presence of necrosis, spindling of tumor based on the presence of necrosis, spindling of tumor cells, vescicular nuclei with large nucleoli, increased cells, vescicular nuclei with large nucleoli, increased mitotic activity, high nuclear to cytoplasmic ratio and mitotic activity, high nuclear to cytoplasmic ratio and pleomorphism. Neoplasms that meet three or more of pleomorphism. Neoplasms that meet three or more of these criteria can be classified as histologically malignant. these criteria can be classified as histologically malignant. Our 3Our 3thth case completely satisfies the reported criteria. case completely satisfies the reported criteria.

Our results could also suggest that, in the absence of Our results could also suggest that, in the absence of “strictly malignant” morphological criteria, the diagnostic “strictly malignant” morphological criteria, the diagnostic immunealgorithm has no prognostic relevance.immunealgorithm has no prognostic relevance.

Finally in the 3Finally in the 3th th cases observed, in which Ki-67 presents cases observed, in which Ki-67 presents an increased proliferative index, might be able to define a an increased proliferative index, might be able to define a high malignant potential GCT. high malignant potential GCT.

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2.2. Miracco C. et al. Miracco C. et al. Granular cell tumor with Granular cell tumor with histological signs of malignancy: report of a histological signs of malignancy: report of a case and comparison with 10 benign and 4 case and comparison with 10 benign and 4 atypical cases. atypical cases. Br J Dermathol 1999, 141 (3): Br J Dermathol 1999, 141 (3): 573-575.573-575.

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