Granular cell tumor of the penis shaft: case report and literature review

Introduction
Granular cell tumor (GCT), a soft tissue neoplasm believed to be of nerve sheath origin, is reported more often in the female external genitalia (1,2). The occurrence of this tumor in the male external genitalia is very uncommon. This paper presents a case of GCT of the penis shaft in a 31-year-old man.

Case report
The patient was a 31-year-old man, with a history of surgically repaired cheilognathopalatoschisis, who was referred in our hospital for evaluation of a painless penile mass. He observed this slowly growing mass 6 months previously, without any subjective symptoms except psychogeneous disorders of sexual dynamics. There was no history of local trauma or infections.
On physical examination the patient was found to have a small ovoid mass, 20x10mm in diameter, at the left base of the penis. The mass was firm on palpation with no fixation on the neighboring tissue, with no inflammatory signs. No other lesions on his external genitalia was noticed nor lymphadenopathy. During the surgical examination, the lesion was situated on the postero-lateral aspect of the left cavernous body, within the penis base, above the albuginea tunica, but non-adherent to it. The lesion was completely excised under loco-regional anesthesia. The surgical specimen was an ovoid gray-white, elastic mass, of 10 x 5 mm, without covering epithelial structures.
Microscopically, on hematoxylin-eosin stained slides the lesion presented itself as a nodular unencapsulated mass with ill defined margins, composed of irregular polygonal cells disposed in variable sized nests, trabeculae and cords with limited infiltrative growth, perineural involvement and microscopic interference of the resection limits. The cells had small round, slightly variable sized nuclei with small nucleoli, variable defined cell borders and abundant granular eosinophilic cytoplasm (Fig. 1). There was no mitotic activity. Immunohistochemical (IHC) staining for S100 protein showed a diffuse positive reaction in the cytoplasm of tumoral cells (Fig. 2). The tumor cells were devoid of reactivity for cytokeratin, smooth muscle actin, desmin and prostate specific antigen (PSA). On the basis of morphological and IHC data a diagnosis of GCT was established. The examination 3 and 6 month later revealed a healing scar without any sign of persistent, recurrent or metastatic disease.
The case described is the only location of a GCT at the penile level encountered in the Pathologic Department of Timisoara County Hospital’s casuistry in the last 15 years, and as far we know, the only case reported in the Romanian medical literature.

Discussion
The granular cells tumor has been first described by Abrikossof, in 1926 (3), who suggested the muscular nature of the tumor cells, hence the initial name of "granular cell myoblastoma”. The subsequent histochemical/IHC and electron microscopy studies have pleaded for the origin of the lesion in the Schwann cells.
GCTs are soft tissue neoplasms frequently encountered in the skin, subcutis, smooth and striated muscle, particularly in the head and neck region (1,2). Cases involving the genitourinary tract are most often reported in woman, in the vulva and clitoris (4,5). In the male genitalia, the tumor is seldom found, with 3 cases reported at the scrotum level, 2 as unique lesions (6, 7) and one as multicentric lesion (8) and other 10 cases described until 2005 involving the penis (6, 9-17). In 2005, Laskin and coworkers (18) described 9 additional cases of GCT of the penis. From a total of 19 cases, 7 occurred in the superficial tissue of the penile shaft, 5 on the prepuce, 4 on the corona, 2 on the glans and 1 in the corpus cavernosum, under the tunica albuginea. Table 1 includes the reported cases of GCT, including our case.
At the penile level, the tumor is more commonly reported in young adults, such as this case, respectively a 31-years old man, but it can be seen at older age, in the 5th and 6th decade (range between 5 and 60 years) (Table 1). From the cases reported till now, only 2 were diagnosed in children, one of 8-years old (13) and another 5-years old (14). By clinical characteristics and size, the tumor which is the subject herein corresponds with the aspects described in the literature in most penile GCT: painless lesion, with slow growth, pointed by stagnation periods, with nodular or plaque-like appearance, with generally reduced sized (0,4 mm - 2,5cm), non-encapsulated, firm consistency, seldom soft, and variable color: pale tan, yellow or whitish-gray. The rapid growth of the lesion, pain or intermittently discharges is seldom associated with penile GCT (18). Most often penile GCT is mobile against the surrounding tissues and covered by skin or mucous membrane without significant macroscopic changes, except one case described in the literature in which the lesion was ulcerated (18). The tumor can be either well or poorly circumscribed, infiltrative, aspects without any impact on recurrence (18). For the cases described in the literature, the period of time passed from the discovery of the lesion until its excision was variable, the average being several months (between 5 days and 6 years) (6,14,15,16,17,18). Usually, GCT is solitary, both in penile location as well as in other sites. In male genital area is reported a case of scrotal multi-centric GCT (8) and another case in which penile prepuce tumor coexisted with other identical lesions in the groin and pubic regions (18).
The nature of the tumor can not be established based on clinical and gross examination, so before surgery, the tumor is seldom suspected, being usually confused with an epidermal or sebaceous cyst, a condyloma, a leiomyoma or even with a malignant tumor (18).
The exact diagnosis represents the attribute of the microscopic examination on routine stains, usually fulfilled with additional histochemical/IHC investigations and/or electron microscopy. The pathological characterization can be done in most cases based on data provided by the routine stains. Although in the case presented herein, the polygonal appearance of the cells with slight variation of the nuclear size, and the presence of the cells in the perineural spaces could suggest a metastasis of a prostatic carcinoma, the young age of the patient and the lack of PSA reactivity, in conjunction with the positive reaction of tumor cells for S100 protein imposed the diagnosis of GCT. From this point of view it is interesting the case of a 53-years old patient with a penile GCT synchronous with a prostatic cancer, to which IHC techniques excluded a possible penile metastasis from the carcinoma of the prostate (16).
Immunohistochemical, the cells of GCT are positive for S100 protein, neuron-specific enolase, vimentin, Leu 7, peripheral nerve myelin proteins (15,16,18) and are negative for actin, desmin, neurofilaments, glial fibrillary acidic protein, cytokeratin (19,20), which advocate for the origin of tumor cells in Schwann cells. It is considered that, in the presence of the suggestive aspects on routine stain and in the absence of unusual histological aspects and/or malignancy features, it is enough the positive reaction for S100 protein (a dymeric protein present in the normal Schwann cells, involved in the calcium metabolism), for the correct diagnosis (6,16), being thus unjustified a more ample IHC study. Although according to some authors the presence of the tumor cells next to the nerve fibers could be an argument for the origin of the lesion in the Schwann cells (13), other authors consider that the perineural arrangement of tumor cells, similar to the disposition around the sweat glands and dermal smooth muscle fibers is rather a proof of involvement of these structures (6).
Laskin and coworkers (18) have the merit of performing the most extensive IHC study of penile GCT, with results that indicate an intense positive reaction for S100 protein in more than 50% of tumor cells (in 5 out of 9 cases). All 5 tumors tested for low-affinity nerve growth factor receptor showed intense positive membrane and cytoplasmic reaction, facilitating, along with the reaction for S100 protein, the identification of cells with perineural arrangement and those from the limits of resection. Four of the 6 tumors assessed for calretinin showed positive nuclear and poor cytoplasmic reaction, focal in 3 cases. None of the tumors was positive for CD34, neurofilament protein or EMA.
The covering epithelium of GCT presents some aspects of squamous hyperplasia of varying degrees, up to pseudo-epitheliomatous hyperplasia, issues that could not be assessed herein, where the surgical excision didn’t contained fragments of overlying epithelium.
Due to the rarity of this lesion in certain localization is compulsory to differentiate it from other lesions/tumors with granular cells: xanthogranuloma, histiocytoma, rhabdomyoma, metastatic prostate carcinoma (17).
The GCT’s evolution is generally benign. There have been reports of local recurrence usually attributed to inadequate excision, so the recommended treatment is complete excision of the lesion with free edges of tumor and surveillance (14,15,16). For cases of penile GCT reported until now, treatment consisted in excision of the lesion except one case to which circumcision was practiced (10). It is worth mentioning that even in the case of tumors with positive margins supervised for a long period of time (between 6 months and 28 years) have not been reported persistency of tumor, local recurrences or metastases, possibly related to vascular and nervous terminations injuries during the surgical excision, so that, the clinical follow-up seems to be enough for this category of patients (15, 16, 17, 18). Considering the penile location, which is a sensitive area in functional and cosmetic terms, there is the opinion that, in the intention to preserve as much normal tissue as is possible, the tumor is suitable for the excision by the Mohs Micrographic Surgery (15).
Based on morphological and clinical criteria proposed by Fanburg-Smith (21), GCT can be classified as benign, atypical or malignant. Accordingly to this classification, with the exception of a single tumor in the casuistry of Laskin and coworkers (18), which was classified as atypical GCT, other cases presented the typical GCT aspects, with some slight focal nuclear atypia. The malignant evolution, reported in a reduced percentage of cases of GCT (21,22), was not reported in the case of genital and penile localization (14,17). The potential for malignant evolution of a GCT is suggested by the following aspects: necrosis, spindling of the cells, increased nuclear-cytoplasmic ratio, vesicular pleomorphic nuclei or increased mitotic activity (> 2 mitoses/10HPF) (1; 21).
In conclusion, the GCT is extremely rare in the male genital area. Lesion described by us is the solely met in the male external genitalia in the Pathology Department of County Hospital in Timisoara within a period of time of 15 years and, by our knowledge, it is the sole case reported in the Romanian medical literature. In the absence of some particular histological features, the morphological aspects on routine stains, completed by the IHC reaction for S100 protein, are sufficient for the histopathological diagnosis.

References
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