Melanotic Neuroectodermal Tumor of Infancy Presenting With Fast-Growing Scrotal Swelling

Introduction

Melanotic neuroectodermal tumor of infancy (MNTI), also known by a variety of names, including melanotic progonoma, retinal anlage tumor, retinoblastic teratoma, and melanotichamartoma, is a rare, rapidly growing, pigmented neoplasm of neural crest origin. Majority of cases occur during the first year of life; the most commonly affected anatomic site is the maxilla, followed by the skull, brain, and mandible; males and females are approximately equally affected; and the median age at diagnosis is 4.3 months in males and 4 months in females. ¹ MNTI is extremely rare in the epididymis and testis. To the best of our knowledge, only 24 cases in the epididymis^2–9 and 2 cases involving testicle^10,11 have been reported in the literature. Its rarity, and rapid and infiltrative growth pattern and variable histological features pose a diagnostic challenge. The common causes of acute scrotal swelling in infants include torsion, trauma, infections, inguinal hernia, neoplasms, spermatocele, and hydrocele.

Case Report

A previously healthy, 3-month-old, full-term male, with a history of worsening hemiscrotal swelling one week, was transferred to us. An outside ultrasound report noted a left scrotal abnormality with reduced flow, most likely testicular torsion. He had no fever, vomiting, dysuria, or hematuria. Maternal, birth, and family history were unremarkable. On arrival, physical examination revealed left hemiscrotal swelling, a firm, nontender, non-erythematous, and non-transilluminating left scrotal mass pushing over to the right side. The right testicle was palpable and soft without mass. No other abnormal physical examination findings were noted. Laboratory investigations revealed slightly elevated LDH (1020 U/L) and normal ß-HCG and alpha-fetoprotein. A repeat testicular ultrasound demonstrated heterogeneous appearance to the left testicle that was suggestive of a mass versus hematoma/testicular fracture versus delayed or subacute testicular torsion.

Preoperative differential diagnosis included scrotal hematoma versus hematoma with testicular torsion versus testicular/scrotal malignancy. An inguinal incision was made, and the spermatic cord structures were controlled. The left testicle was enlarged, firm, and encapsulated. The epididymis was indistinguishable from the testis grossly, and no evidence of torsion was noted. A radical orchiectomy with excision of the entire spermatic cord was performed. The testis was bivalved in the operating room revealing abnormal soft tissue with necrotic material and old blood, raising concern for malignancy.

Macroscopically, the left orchiectomy specimen weighed 29.6 g and measured 5.0 × 3.6 × 3.1 cm with a spermatic cord extending 4.2 cm in length by 0.7 cm in diameter. On section, there was a mass (5.0 × 3.6 × 3.0 cm) occupying almost entire testicle with white tan solid areas in periphery, central cystic cavitation along with areas of pigmentation, necrosis, and hemorrhage (Figure 1(a)). No residual testicular parenchyma was grossly identified. The tumor was confined to the testicle without invasion into spermatic cord or tunica albuginea.

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Figure 1.

(a), Gross photograph of the left orchiectomy reveals a mass occupying almost entire testicle with white tan solid areas in periphery, central cystic cavitation along with areas of pigmentation, necrosis and hemorrhage. b–c, Low- and high-magnification views of tumor. The tumor is composed of predominantly nests/sheets of small round cells in a background of fibrotic tissue with focal myxoid change. The small round cells have hyperchromatic nuclei, salt and pepper chromatin, inconspicuous nucleoli and scanty cytoplasm. Admixed with small round cells are scattered small- to medium-sized epithelioid cells with pale nuclei with finely dispersed chromatin, prominent nucleoli and pale cytoplasm. Some epithelioid cells contain a few fine brown cytoplasmic pigment granules (arrow in c). (d), Nests of tumor cells infiltrating the epididymal structures. (b–d, Hematoxylin-eosin stain; Original magnification: × 100 for B, × 400 for (c), × 200 for d.)

Histological examination revealed a cellular tumor in a background of necrosis, hemorrhage, and degenerative cystic changes. The tumor was composed of predominantly nests/sheets of small round cells in a background of fibrotic tissue with focal myxoid change (Figure 1(b)). The small round cells had hyperchromatic nuclei, salt and pepper chromatin, inconspicuous nucleoli, and scanty cytoplasm. Admixed with small round cells were scattered small- to medium-sized epithelioid cells with pale nuclei with finely dispersed chromatin, prominent nucleoli, and pale cytoplasm. Some epithelioid cells contained a few fine brown cytoplasmic pigment granules (Figure 1(c), arrow). Scanty remaining epididymis tubules were surrounded by two tumor cell populations with more obvious pigmentation (Figure 1(d)). Rare seminiferous tubules were also present. No rete testis was identified. There was no evidence of lymphovascular invasion. Immunostaining showed the small round cells were positive for synaptophysin (Figure 2(a)), NSE (Figure 2(b)), and CD56. The scattered epithelioid cells were positive for HMB45 (Figure 2(c)) and AE1/AE3 (Figure 2(d)). All cells were negative for CD45, desmin, CD99, PGP 9.5, SALL4, glypican 3, CD117, TdT, CD30, and hCG. The final diagnosis was MNTI of the testis and epididymis.

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Figure 2.

Immunostaining pattern. The small round cells are positive for synaptophysin (a) and NSE (b); the epithelioid cells are reactive for HMB45 (c) and AE1/AE3 (d). (Original magnification: × 400 for a–d).

Discussion

MNTI often presents as an invasive, fast-growing lesion, suggesting a clinical impression of infection, hematoma, torsion, or malignant neoplasm. Infection usually has fever and other symptoms, which our patient lacked. Testicular torsion, torsion of testicular/epididymal appendages, and trauma with testicular rupture/scrotal hematoma should be considered in the differential diagnoses of acute scrotum in this age group. Primary tumors of the testicle are rare in infants. Table 1 summarizes the differential features of primary testicular tumors of infancy. In this case, peripheral primitive neuroectodermal tumor arising in teratoma and germ cell tumors were considered. However, our patient had normal alpha-fetoprotein and HCG; there was no histological evidence of teratoma; and germ cell immunomarkers such as SALL4, glypican 3, CD117, CD30 and hCG were all negative.

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Table 1.

Differential Features of Primary Testicular Tumors of Infancy.

Tumors	Common site	Typical cut surface	Histopathological hallmarks	Positive immunostaining
Juvenile granulosa cell tumor	Testis	Partially encapsulated, cystic with yellow-white solid areas	Variably sized and shaped follicular-like cystic spaces filled with mucoid material	Inhibin, calretinin
Yolk sac tumor	Testis	Gray to yellow, often mucoid	Variable patterns, Schiller-Duval bodies, intracytoplasmic eosinophilic hyaline globules	AFP, AE1/AE3, Glypican 3, SALL4
Mature teratoma	Testis	Heterogenous, may have hair	Cellular components derived from 2 or 3 germ layers	NA
Embryonal rhabdomyosarcoma	Paratesticular	Gray-white glistening	Variable numbers of strap cells and bizarre “tadpole” cells	Desmin, Myogenin, MyoD1
Melanotic neuroectomal tumor of infancy	Epididymis	Tan yellow to black	Two cell populations with pigmentation	HMB45, AE1/AE3, synaptophysin, NSE

MNTI is typically 2–4 cm in maximum dimension at the time of diagnosis. The tumors vary in color from tan-yellow to dark red with or without areas of pigmentation. Histologically, MNTI is characterized by biphasic morphology. It is composed of two distinct cell populations: small round cells with oval hyperchromatic nuclei and scant cytoplasm, and large melanin-containing cuboidal epithelioid cells. Mitoses may be present, usually in small round cell component. Pleomorphism is usually not seen in this kind of tumor. MNTI demonstrates a multiphenotypic (epithelial, neural, melanocytic) immunostaining pattern. A previous study ¹² described small round cells positive for NSE (7/12), CD56 (9/12), synaptophysin (4/12), glial fibrillary acidic protein (GFAP) (3/12), and S-100 (2/12), as well as epithelioid cells positive for cytokeratin (12/12), HMB (12/12) and EMA (4/9). Although the histology and immunostaining pattern of MNTI are quite characteristic, the diagnosis can be challenging for pathologists due to its rarity, variable histological appearance, and outside the head and neck region.

MNTI involving epididymis and testis is extremely rare. In 1995, Calabrese et al. ² did a literature review of all published 17 epididymal MNTI cases. Table 2 summarizes 7 additional cases reported since 1991 and 3 cases involving testis. In the current case, the small round cells are predominant, and melanin pigment is inconspicuous at low magnification. As a result, our first impression was small round blue cell tumors, such as neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma, or lymphoma. Negative immunohistochemical staining for PGP 9.5, desmin, CD99, CD45, and TdT ruled out those possibilities. Therefore, in apparent small round blue cell tumors in the testicle in infants, it is crucial to keep the existence of testicular MNTI in mind and to identify a pigmented epithelioid cell population.

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Table 2.

Additional Epididymal Cases and Cases Involving Testis.

Reference	Age (months)	Tumor location	Tumor size (cm)	Surgery	Metastasis	Follow-up
Siracusano et al. 3	8	Epididymis	1.5	Radical orchiectomy	No	28 months
Diamond et al. 4	6	Epididymis	1.0	Radical orchiectomy	No	1 year
Jurincic-Winkler et al. 5	6	Epididymis	2.0	Simple orchiectomy	No	4 years
Kobayashi et al. 6	4	Epididymis	1.4	Radical orchiectomy	No	4 months
Toda et al. 7	5	Epididymis	1.5	Simple orchiectomy	NA	NA
Desai et al. 8	18	Epididymis	1.0	First epididymectomy, recurrence at 9 months, then simple orchiectomy	No	NA
Pantanowitz et al. 9	6	Epididymis	1.8	Simple orchiectomy	NA	NA
Ricketts et al. 10	3	Testis and epididymis	2.5	Simple orchiectomy	No	4 months
Denadai et al. 11	8	Testis and epididymis	1.8	Simple orchiectomy	No	30 months
Current case	3	Testis and epididymis	5.0	Radical orchiectomy	No	5 months

The cell origin of MNTI has been the subject of controversy. The immunostaining profiles and ultrastructural studies suggest that MNTI is derived from the neural crest. The fact that MNTI occurs in testis/epididymis should not add to the confusion concerning its cell origin, as it is well known that immature teratomas of testicle can have neuroectodermal element. The mechanism of pathogenesis of MNTI is largely unknown. Recently, Gomes et al. ¹³ showed that one of three maxilla MNTIs harbors the BRAFV600E mutation, providing first genetic information on MNTI.

Although MNTI is widely accepted as a potentially malignant neoplasm, given its rapid and locally infiltrative growth, early treatment is very important. Most MNTIs are effectively managed by radical surgical excision. For testicle MNTI, simple orchiectomy appeared to be curative. ¹¹ One section per centimeter of maximum tumor dimension may be necessary. The stage system is not available. Due to its potential for recurrence ⁸ and extremely rare malignant transformation, ¹⁴ clear margins and follow-up is recommended. Time to recurrence ranged from 10 days to 2 years. ¹ No reliable morphological and immunohistochemical features predict recurrence or metastasis. ¹⁵ For our case, despite a history of rapid growth, at 5 months of follow-up, there is no recurrence or metastasis.

We reported this case to increase the clinical awareness of this rare entity in the testicle. MNTI should be included in differential diagnosis in infants presenting with acute scrotum or rapidly growing hemiscrotum.