Introduction: Neurocutaneous melanosis, defined as neurocutaneous melanocytosis, is a rare congenital nongenetic neurocutaneous syndrome [8,11] characterized by the presence of multiple or large cutaneous nevi and hypermelanocytic sis of the central nervous system. In 1861, R okitansky first reported describing a 14-year-old neurocutaneous dark girl with clinical features [12], while the N CM formulation was made by Van. proposed by Bogle in 1948, its pathogenesis has not been fully clarified. Melanocytes naturally exist in the central nervous system, and usually remain static, but in N CM, the embryonic neural ectodermal morphology of a wrong change, causes the growth and migration of melanocytes, and melanocytes on the meninges can occur asymptomatic benign hyperplasia (asymptomatic NCM), however, this benign hyperplasia, secondary to cerebrospinal fluid circulation disorders and cerebral hemorrhage, intracranial nerve abnormal performance (symptomatic NCM), resulting in the abnormal nervous system [13]. Clinical manifestations of neurocutaneous melanosis (NCM) [14,15]: (1) congenital hairy surface of melanocytic nevus. (2) There are small "satellite" nevus around large pigment nevus, or more black nevus or nodules. (3) Melanocyte infiltration in the brain parenchyma and leptominginges can be found on magnetic resonance imaging or pathological tissue sections. In 1972, FOX first proposed the clinical diagnostic criteria of NCM, but Kadonaga proposed the current clinical application in 1991 [16]: large skin area in adults (20cm; neonatal head diameter 9cm or 6cm) multiple (> 3) congenital nevi with benign or malignant central nervous system; no malignant melanoma lesions in the body (including skin). About 2 / 3 of the patients with neurocutaneous lesions accompanied by congenital huge melanin nevus, which is characterized by black pigment nevus at birth, a dotted distribution of the body, including the head, shoulders, limbs, etc., the surface with black thick hair, also known as animal skin nevus, but this skin pigment nevus is usually benign. Congenital giant melanotic nevi occurring on the skin develop malignant melanoma in 2% to 13%, and those with satellite focal areas greater than 50 * 50cm or located around the midline of the trunk, or the probability of developing neurocutaneous dark lesions significantly increases in [17]. Based on the above diagnostic criteria, although our case did not have a large pigment nevus, it was highly suspected of N CM, and the pathological diagnosis was obtained through surgery.
When the patient was born, the body was not covered with a large area of huge black pigment nevus like other patients, but was distributed to the trunk and limbs. The diameter of the mole was about 2 to 3 cm. As the patient grew, the center of the mole began to grow thick hair and the number increased. According to the pathological diagnosis, the skin surface lesion is benign. Chest CT and abdominal ultrasound excluded the possibility of metastatic melanoma. The growth of this small or medium cutaneous nevus, suggests that the probability of this cutaneous nevus turning to malignant melanoma is very low, but as the number of this sporadic nevus increases, it may still cause the [18,19] of malignant melanoma.
Incidence: The actual incidence of NCM is unknown, but is reported in the literature to be around 7% [20]. NCM cases in children are more common, while adult N CM cases are very rare. Patients with congenital giant nevus belong to the high-incidence population of NCM, About 2 / 3 of the NCM patients have congenital giant nevi, But the risk of final progression to symptomatic NCM is unclear [20], In the clinical follow-up of patients with congenital giant nevi with a history of 2 – 8 years, Foster et al [21] found that only one of 46 patients later developed neurological symptoms, And the location and size of giant nevi does not appear to correlate entirely with the abnormalities identified by MRI, This also predicts an increased risk of both cutaneous and primary CNS melanoma in patients with congenital giant nevi, But it does not necessarily indicate a poor prognosis.
Neurocutaneous melanosis includes cutaneous melanin-induced lesions and intracranial melanoma. Melanocytes are usually located in the leptomeningeum, and can also be located at the base of the skull, the basal surface of the brain, the anterior surface of the optic cross, and the brain stem, and, under certain conditions, are converted into the tumor cell, invading the internal [22] of the brain tissue. In 2021, the World Health Organization (WTO) classified meningeal melanocytic hyperplasia and meningeal melanomatosis and meningeal melanocytic tumors, and meningeal melanomas according to the D NA mutation site. This is more accurate than the 2016 World Health Organization CNS tumor classification [24]. Meningeal melanocytosis and meningeal melanomatosis are relatively benign lesions relative to malignant melanoma, but the prognosis is also poor because of the possibility of malignant changes [25].
Genetic aspect: Neurocutaneous melanosis (NCM) is mostly sporadic, and all the cases reported at home and abroad have no familial genetic background [26]. Currently, some researchers believe that congenital giant melanin nevus is genetically related to [27], while congenital giant melanin nevus is highly related to [28,29] with N CM patients, but Bittencourt believes that the incidence of its development into N CM is very low in [30]. Therefore, the etiology and genetics of congenital giant pigment nevi and N CM need further investigation. However, due to the high mortality in pediatric N CM patients, low N CM prevalence of N CM and no uniform epidemiological data, and a proportion of N CM patients having no obvious pigmented nevus, the above factors lead to the lack of genetic studies on N C M patients. We report a patient in whom both parents and children were healthy, with no obvious pigmented nevus, and the patient was born without a large fusion sheet pigmented nevus, but a sporadic pigmented nevus, which may be a factor in the late onset of the patient.
Imaging: Although melanoma contains melanin particles containing paramagnetic substances, which can shorten the time of T1 and T2 imaging, melanoma has the typical short T1 high signal and short T2 low signal imaging characteristics on M RI. But using MRI alone, cannot identify diffuse melanocytosis, meningeal melanocytostoma, and malignant melanocytic melanoma. However, according to the number of melanocytes, four imaging types are shown as [31] on M RI: (1) melanin type; (2) non-melanin type; (3) mixed type; and (4) blood type. In this paper, the patient's enhanced M RI showed: the right frontoparietal sulcus and meninges enhancement, with no significant occupation. C T showed the right frontoparietal sulcus, cerebral fissure and cerebral sickle high-density shadow, and hydrocephalus. According to the above imaging classification, the patient belongs to the melanin type, but the patient had been misdiagnosed as subarachnoid hemorrhage in the local hospital and was treated.
Pathology All melanocytes in pathological immunohistochemistry showed vimentin (V IM), S-100, and H MB-45 positive. S-100 has high sensitivity and H MB-45 has high specificity, and the high expression of S-100 protein may suggest enhanced metabolic proliferative capacity. The positive rate of epithelial nuclear antigen proliferation is important for distinguishing malignant melanoma from benign melanoma [32]. In this paper, microscopic H E staining showed growing epithelial-like cells with significant nucleoli and scattered melanin particles, and no clear nuclear division. Immunohistochemistry showed S-100 (+), HMB-45 (+), M elan A (+), EMA (-), and K I-67 (+ 5%).
The statistics of the domestic report literature review show that NCM patients can be classified as symptomatic and asymptomatic according to the presence or absence of CNS clinical symptoms, and this classification helps judge the prognosis of N CM in [33]. For symptomatic NCM patients, there are two peaks: the first is that in the first or second year of birth, newborns and infants usually present with acute increased intracranial pressure, which can be accompanied by epilepsy, developmental delay, cranial nerve palsy, and other symptoms [9,34]. The second peak is around [35] from 20 to 30 years old. Patients with late-onset of CNS symptoms usually present with solitary intracranial space-occupying lesions with slow growth rate, focal seizures, local sensorimotor impairment, and speech difficulties as major [36-38]. Our reported case showed a walking disorder at the age of 7 years, so we suspect that the patient was already sick in childhood, but why the symptoms did not continuously worsen is something we currently cannot explain.
By searching wanfang, CNKI, and PUBMED, we reported a total of 34 Chinese adult NCM patients, aged 19 to 59 years, on average 26.9 years, including 23 men (67.6%), 11 women (32.4%), 2 diffuse melanocytosis (5.8%), 31 malignant melanoma (91.1%)) and 1 mixed nevus (3.1%).29 Patients developed satellite nevus (73.5%), and 5 patients had uncertain satellite nevus status (26.5%). Among them, 33 cases (97.0%) had obvious intracranial lesions, and 1 case had no obvious intracranial lesions (3.0%). CNS symptoms: 9 patients with increased intracranial pressure (26.4%), 10 seizures (29.4%), 1 hydrocephalus (2.9%), 1 cerebral hemorrhage (2.9%), 1 patient with D andy-Walker malformation (2.9%); 7 patients died at follow-up (20.5%), and the remaining current survival conditions were unknown. The maximum follow-up of 3 years reported that the patient was still alive. Current accurate survival data for these patients require further follow-up.
In our group of cases, the pathological result was twice the number of male adult NCM patients. Although this difference was not statistically significant due to the small sample number, the question arises: is there a correlation between estrogen and the incidence of adult NCM patients? The 2020 US Surveillance, Epidemiology, and Prognostic Outcomes database (SEER) analysis indicate that the incidence of melanoma in men is two times higher than [39] in women over the past three decades. Studies have shown that male and female melanoma patients also have significant differences in prognosis, and women have a significant survival advantage over men [40]. Studies have also shown that: melanocytes produce a huge congenital skin melanocytic nevus due to the NRAS gene mutation and the BRAFV600E gene mutation, and the soft brain membrane melanocytosis through the N RAS gene mutation, activates the MAPK, PI3K / Ak t pathway, into the nervous system melanocytic melanoma [41]. Estrogen is a steroid hormone secreted by the ovary and placenta, with a wide range of physiological functions, while estrogen can also cross the blood-brain barrier in different parts of brain tissue to exert a neurological protective role [42]. Estrogen exerts biological effects in related target tissues mainly by binding to the estrogen receptor (ER). Among them, ER and FR are the main types. It was shown that ER has significant antitumor activity and suppresses and develops [43] in NRAS mutant melanoma cells by inhibiting the activation of M APK / ERK or P I3K pathways. Therefore, we can infer that increased estrogen levels can delay the occurrence and progression of melanocyte deterioration.
For neurocutaneous melanosis, the treatment option is mainly based on the presence of obvious intracranial space-occupying lesions. Existing treatment options include neurosurgical interventions, whole-brain radiotherapy, chemotherapy, immunotherapy, gene therapy, and combination therapy. According to our statistics, 10 patients underwent surgical resection (29.4%), 24 patients received non-surgical treatment (70.6%), 3 deaths (30.0%)), with a maximum follow-up of 3 years, 4 deaths (16.6%), but 18 deaths in non-surgical treatment, including non-surgical NCM patients.
For intracranial localized lesions, we recommend microscopic surgical resection. For diffuse intracranial lesions, although melanoma cells can be found by cerebrospinal fluid examination, patients often have more amount of cerebrospinal fluid, including the symptoms of increased intracranial pressure and hydrocephalus, and the risk of sudden cerebral hernia during operation. Therefore, we recommend using the stereotactic brain tissue biopsy method. Our case is that the surgical protocol of stereotactic brain biopsy obtained clear pathological results. Many patients with N CM were treated with postoperative chemoradiotherapy. However, the sensitivity of chemoradiotherapy is questionable, although stereotactic radiotherapy has reported a better prognosis than whole-brain radiotherapy. However, hydrocephalus caused by arachnoid adhesion is easy to occurs after radiotherapy. If these patients take the ventricle-abdominal shunt surgery, there will be the possibility of melanocytes blocking the shunt tube and intraperitoneal implant transfer, how to solve it? We need to think about it and solve it in advance
Our patient was followed up for 6 months without symptom onset or new symptoms and is still in follow-up. Therefore, for children with a congenital giant cutaneous nevus, the CNS examination was performed early to exclude N CM. Once found, neurosurgical intervention is recommended to clarify the pathological diagnosis. However, there is no effective treatment, and the prognosis is extremely poor. But we believe that with the development of medical technology, better treatments will emerge in the future.