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Pathology International 2015; 65: 100–105
doi:10.1111/pin.12238
Case Report
Leptomeningeal melanomatosis associated with neurocutaneous melanosis: An autopsy case report
Mai Matsumura,1 Koji Okudela,1 Yoko Tateishi,1 Shigeaki Umeda,1 Hideaki Mitsui,1 Takehisa Suzuki,1 Takashi Nakayama,2 Yoshiaki Inayama3 and Kenichi Ohashi1 Department of Pathology, Yokohama City University Graduate School of Medicine, 2Department of Pathology, Saiseikai Yokohamashi Nanbu Hospital and 3Department of Pathology, Yokohama City University Medical Center, Yokohama, Japan 1
An autopsy case of leptomeningeal melanomatosis associated with neurocutaneous melanosis (NCM) involving a 44-year-old male is reported. The autopsy showed that the leptomeningeal surface of the brain and the spinal cord were covered with a diffuse black lesion. A histological examination detected diffusely distributed, proliferating, melanincontaining cells and demonstrated that the lesion consisted of three different components; i.e. regions of melanomatosis, melanocytosis, and melanocyte hyperplasia. In the leptomeningeal melanomatosis component, tumor cells with pleomorphic nuclei and prominent nucleoli had infiltrated into the cerebral parenchyma via Virchow–Robin spaces. The Ki-67 labeling index and the nuclear accumulation of p53 and p16 protein were immunohistochemically examined in each component. The Ki-67 labeling indices of the melanomatosis, melanocytosis, and melanocyte hyperplasia components were 8.7%, 0.8%, and 0%, respectively. Immunostaining of nuclear p16 produced a negative result in the melanomatosis component, but positive results in the melanocytosis and melanocyte hyperplasia components, whereas nuclear p53 expression was not detected in any of the components. This case suggests that p16INK4/CDKN2 may play a significant role in progression of leptomeningeal melanocytic neoplasms. We also reviewed previously reported cases of leptomeningeal neoplasms associated with NCM and discussed the relationship between the biological behavior and proliferative activity of such lesions.
Primary melanocytic neoplasms of the leptomeninges are rare, but often develop in patients with neurocutaneous melanosis (NCM). NCM is characterized by the excessive proliferation of melanocytes in the leptomeninges and skin. Embryologically, neural crest-derived precursor cells differentiate into a number of cell types including leptomeningeal cells, glial cells, adrenal medullary cells, and melanocytes. NCM is considered to be caused by an embryological error in the development of the neuroectoderm, resulting in a form of congenital dysplasia involving the skin and leptomeningeal melanoblasts.1 Primary melanocytic neoplasms of the leptomeninges include melanocytoma, malignant melanoma (MM), melanocytosis, and melanomatosis.2 Melanocytoma and MM form masses, whereas melanocytosis and melanomatosis produce diffuse lesions. The diffuse lesions produced by melanocytosis lack histological signs of malignancy. On the other hand, those produced by melanomatosis exhibit the characteristic cytological features of malignancy. We experienced a rare autopsy case of leptomeningeal melanomatosis associated with NCM. Here, we describe this case and discuss the relationship between the biological behavior and pathological findings of such lesions.
Key words: melanoma, melanomatosis, neurocutaneous melanosis, p16, p53, proliferation
CLINICAL SUMMARY
Correspondence: Mai Matsumura, MD, Department of Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Email: [email protected] Received 29 August 2014. Accepted for publication 6 November 2014. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
A 44-year-old Japanese male suffered a seizure and a disturbance of consciousness due to hydrocephalus. He had multiple congenital cutaneous nevi with or without hair on his trunk and lower extremities (Fig. 1a). Although he had been healthy for most of his life, he had suffered from neck pain and memory loss for the past few years. Gadoliniumdiethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced magnetic resonance imaging detected diffuse linear highintensity lesions on the surface of his brain and spinal cord. A cytological examination of the patient’s cerebrospinal fluid,
Leptomeningeal melanomatosis with NCM
which was obtained via a lumbar tap, showed atypical cells containing cytoplasmic melanin granules (Fig. 1b). A brain biopsy detected MM cells, which had spread into the subarachnoid and Virchow–Robin spaces (Fig. 1c). Although it was not confirmed whether the lesion had invaded into the cerebral parenchyma, a histopathological diagnosis of leptomeningeal melanomatosis was made based on the presence of cytological atypia involving pleomorphic nuclei, frequent mitotic figures, and a high Ki67 labeling index (10.8%). Temozolomide chemotherapy and decompression for the hydrocephalus were performed; however, the chemotherapy had little effect on the disease progression, and the patient died of multiple brain hemorrhages 6 months later. Clinically, platelet count and clotting function were within normal limit, and bleeding tendency was not observed.
PATHOLOGICAL FINDINGS An autopsy was performed 5 h after the patient’s death. Multiple cutaneous pigmented nevi (diameter: 1–12 cm) with
Figure 1 (a) Photograph of the large pigmented nevi with hair on the patient’s lower extremities. (b) Cytology of the patient’s cerebrospinal fluid. Melanin-containing atypical cells were observed (arrow, Giemsa stain, ×400). (c) Histology of the brain biopsy sample. Malignant melanoma cells were found on the surface of the brain and in Virchow–Robin spaces (hematoxylin and eosin (HE) stain, × 40).
or without hair were observed on the patient’s trunk and lower extremities. Grossly, the brain was swollen and weighed 1580g (Fig. 2a). In addition, multiple hemorrhages were observed in the brain and subarachnoid space (Fig. 2b). A black lesion covered the surfaces of the brain and the spinal cord (Fig. 2c). Neither primary nor metastatic MM lesions were identified in other organs, including the skin. In the histological examinations, formalin-fixed paraffinembedded tissue sections were cut and stained with hematoxylin and eosin, and luxol fast blue–periodic acid Schiff (LFB–PAS) stain. In the immunohistochemical examinations, formalin-fixed paraffin-embedded tissue sections were incubated with primary antibodies against S-100 (polyclonal; Nichirei Bioscience, Tokyo, Japan), HMB45 (clone HMB4; DAKO, Ely, UK), Ki-67 (clone MIB-1; DAKO), p53 (clone DO-7, DAKO), and p16 (clone E61-14, Roche, Mannheim, Germany). Immunoreactivity was visualized with the Envision detection system (DAKO). The reactions were developed using commercially available AEC (3-amino-9-ethyl carbazole), and counterstaining was performed with hematoxylin.
a
a
Figure 2 (a) Gross appearance of the brain. The brain displayed marked swelling, and a black lesion covered its surface. (b) A cut section of the brain exhibited cerebral hemorrhage (arrow). (c) Cut sections from the thoracic to lumbar cord. The spinal cord was also covered with a thick black lesion. (d) Histology of the melanomatosis component. Melanin-containing tumor cells were observed on the brain surface and in Virchow–Robin spaces. The tumor cells had infiltrated into the cerebral parenchyma, and the border between the tumor and cerebral cortex was unclear (HE stain, × 100). (e) The tumor cells had also infiltrated into the spinal nerve roots (LFB–PAS stain, × 200). (f) Tumor cells had infiltrated into small blood vessels (HE stain, × 400).
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d
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
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c
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c
e
f
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The red of the positive AEC-staining cells could be distinguished from the brown of the melanin-containing tumor cells. The Ki-67 labeling index was calculated as the proportion of Ki-67-positive cells among up to three hundred cells. A histological examination of the patient’s leptomeningeal tissue detected diffusely distributed melanin-containing proliferating tumor cells. The tumor cells filled the subarachnoid spaces of the brain and spinal cord and in some regions they had infiltrated into the cerebral and spinal parenchyma via Virchow-Robin spaces (Fig. 2d,e). The maximum depth of the parenchymal invasion was limited to 1 mm. The bleeding in the brain and subarachnoid space was considered to have been caused by vascular invasion (Fig. 2f). At the invasive sites, the polygonal tumor cells showed marked cellular atypia involving pleomorphic nuclei and prominent nucleoli (Fig. 3a). More than 10 mitotic figures were observed in 10 high-power fields. The tumor cells were positively stained for S-100 and HMB45, and their Ki-67 labeling index was 8.7% (Fig. 4a). However, immunostaining of both p53 and p16 produced negative results (Fig. 4d,g). We diagnosed the invasive parts of the black lesion as leptomeningeal melanomatosis. Melanomatosis accounted for about 70% of the black lesion and was mainly distributed in the temporal lobe and spinal cord. In the parts of the lesion that did not exhibit invasion, the tumor cells showed milder cellular atypia together with mild nuclear pleomorphism (Fig. 3b). These cells contained almost no mitotic figures, and their Ki-67 labeling index was only 0.8% (Fig. 4b). Although p53 immunostaining produced a negative result, strong diffuse p16 positivity was detected (Fig. 4e,h). The tumor cells in the non-invasive regions did not display any malignant features, which was suggestive of leptomeningeal melanocytosis. Melanocytosis accounted for about 30% of the black lesion and was mainly distributed in the parietal lobe and cerebellum. The border between the melanomatosis and melanocytosis components was unclear, and a continuous transition between the different types of cellular atypia exhibited by these two components was observed. Furthermore, benign-looking spindle-shaped mature melanocytes were scattered on the arachnoid membrane around the black lesion (Fig. 3c). Mitotic figures were absent from the melanocytes, which exhibited a Ki-67 labeling index of 0% (Fig. 4c). p53 immunostaining produced a negative result, but strong diffuse p16 positivity was detected, which was indicative of leptomeningeal melanocyte hyperplasia (Fig. 4f,i). A histological examination of the skin lesions detected pigmented nevi of the intradermal type.
DISCUSSION NCM is a rare congenital syndrome in which benign or malignant melanocytic neoplasms of the leptomeninges are found
a
b
c
Figure 3 Histological findings of the (a) melanomatosis, (b) melanocytosis, and (c) melanocyte hyperplasia components (HE stain, × 400). (a) In the melanomatosis component, the tumor cells possessed a large amount of variably pigmented cytoplasm together with large and pleomorphic nucleoli and conspicuous nucleoli. (b) In the melanocytosis component, the tumor cells had smaller round nuclei and contained cytoplasmic melanin granules. (c) In the melanocyte hyperplasia component, spindle-shaped mature melanocytes without cellular atypia were sporadically distributed on the arachnoid membrane.
in the context of large and/or numerous congenital melanocytic nevi. NCM was first reported by Rokitansky in 1861.3 So far, at least 200 cases of NCM have been reported in the English literature, and about 70 cases have been reported in the Japanese literature since 1914. As for autopsy cases, only about 10 cases have been reported in the English literature. In 1972, Fox proposed clinical criteria
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Leptomeningeal melanomatosis with NCM
Figure 4 Immunohistochemical findings of the (a,d,g) melanomatosis, (b,e,h) melanocytosis, and (c,f,i) melanocyte hyperplasia components. The three components were subjected to immunohistochemical analyses of their (a–c) Ki-67 indices, (d–f) p53 and (g–i) p16 expression. Positive cells appear red signal as opposed to melanin brown granules. The Ki67 labeling indices of the melanomatosis, melanocytosis, and melanocyte hyperplasia components were (a) 8.7%, (b) 0.8%, and (c) 0%, respectively. (d–f) p53 was not detected in any of the three components. (g) p16 immunostaining produced a negative result in the melanomatosis component, but (h,i) detected strong diffuse p16 positivity (red-colored) in the melanocytosis and melanocyte hyperplasia components.
a
b
c
d
e
f
g
h
i
for diagnosing the condition.4 The definition of NCM was subsequently refined by Kadonaga and Frieden in 1991 to include:1 1 Large (>20 cm in largest diameter in adult cases) or multiple (three or more) congenital nevi in association with meningeal melanosis or melanoma. In infant cases, congenital nevi on the head that measure 9 cm in diameter and those on the body that measure 6 cm in diameter are considered to meet the criteria for NCM because the projected growth of a lesion’s surface area is assumed to be proportional to the normal skin growth of the body region it lies within. 2 No evidence of cutaneous melanoma except when the examined areas of meningeal lesions are histologically benign. 3 No evidence of meningeal melanoma except when the examined areas of cutaneous lesions are histologically benign. In general, primary melanocytic neoplasms of the leptomeninges are classified into two types, the mass-forming type, such as melanocytoma or MM, and the diffuse type, such as melanocytosis or melanomatosis. The incidence of melanocytoma is 1 per 10 million, and the incidence of MM is 1 per 20 million.5 Diffuse leptomeningeal melanocytic lesions are rarer than mass-forming lesions, although no data regarding their population-based incidence rates are available. The prognosis of diffuse melanocytic neoplasms is poor, even in the absence of histological malignancy,5 and about 50% of patients with
103
diffuse type lesions die within three years of the onset of neurological symptoms.1 NCM patients that display leptomeningeal involvement are at risk of developing MM or melanomatosis, which exhibit estimated prevalence rates of 40–60% among this group.1 As for the background changes that lead to melanomatosis, benign components like melanocytosis or melanocyte hyperplasia are commonly observed in cases of melanomatosis.6 In previous studies, the biological behavior of leptomeningeal melanocytic neoplasms associated with NCM was comprehensively assessed based on data regarding cellular atypia, mitosis, invasion, bleeding, and the Ki-67 labeling index; however, it is still difficult to distinguish between melanocytosis and melanomatosis.6–8 In previous studies of skin melanocytic tumors, the Ki-67 labeling index was reported to be less than 10% in benign tumors, to range from 2–85% (mean: 34%), and generally be above 50% in MM.9 On the other hand, the Ki-67 labeling index of leptomeningeal melanocytic tumors has been reported to range from 0 to 2% (mean: 0.5%) in mass-forming melanocytoma and from 2 to 15% (mean: 7.8%) in massforming MM.10 Moreover, intermediate-grade tumors were defined in the AFIP atlas of tumor pathology, and a Ki-67 labeling index of 1–4% was proposed as one of the criteria for identifying such lesions. However, only 10 cases of leptomeningeal melanocytic neoplasms associated with NCM, including the present one, have been reported in the literature, and previous case reports have not provided much detailed information about the histopathological features, proliferative activity, or prognosis of such lesions.6–8,11–16 The clinical and pathological
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
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Table 1
Review of reported cases of leptomeningeal melanocytic neoplasms associated with neurocutaneous melanosis (NCM) Histopathological features
Cases Malignant tumor 1 [6]
Age Sex
Material
Location
Nuclear form
Bleeding Invasion
Ki67 labeling index
Histological diagnosis
Outcome
33
M
Autopsy Brain, spinal Pleomorphic
+
+
2 [11] 3 [7]
35 9
M F
Biopsy Brain Autopsy Brain
NA NA
NA +
2.54% Melanomatosis D[6M] (1.2–10.5%) 11% Melanomatosis D[31M] High Melanomatosis D[12M]
4 [12] 5 [13]
1 1
M F
Biopsy Surgery
NA NA
NA NA
≥30% ≥80%
44
M
Autopsy Brain, spinal Polygonal
+
+
8.70%
10 3 40 9
F M F F
Surgery Surgery Surgery Autopsy
− − NA −
− − NA −
0% Low
Pathology International 2015; 65: 100–105
doi:10.1111/pin.12238
Case Report
Leptomeningeal melanomatosis associated with neurocutaneous melanosis: An autopsy case report
Mai Matsumura,1 Koji Okudela,1 Yoko Tateishi,1 Shigeaki Umeda,1 Hideaki Mitsui,1 Takehisa Suzuki,1 Takashi Nakayama,2 Yoshiaki Inayama3 and Kenichi Ohashi1 Department of Pathology, Yokohama City University Graduate School of Medicine, 2Department of Pathology, Saiseikai Yokohamashi Nanbu Hospital and 3Department of Pathology, Yokohama City University Medical Center, Yokohama, Japan 1
An autopsy case of leptomeningeal melanomatosis associated with neurocutaneous melanosis (NCM) involving a 44-year-old male is reported. The autopsy showed that the leptomeningeal surface of the brain and the spinal cord were covered with a diffuse black lesion. A histological examination detected diffusely distributed, proliferating, melanincontaining cells and demonstrated that the lesion consisted of three different components; i.e. regions of melanomatosis, melanocytosis, and melanocyte hyperplasia. In the leptomeningeal melanomatosis component, tumor cells with pleomorphic nuclei and prominent nucleoli had infiltrated into the cerebral parenchyma via Virchow–Robin spaces. The Ki-67 labeling index and the nuclear accumulation of p53 and p16 protein were immunohistochemically examined in each component. The Ki-67 labeling indices of the melanomatosis, melanocytosis, and melanocyte hyperplasia components were 8.7%, 0.8%, and 0%, respectively. Immunostaining of nuclear p16 produced a negative result in the melanomatosis component, but positive results in the melanocytosis and melanocyte hyperplasia components, whereas nuclear p53 expression was not detected in any of the components. This case suggests that p16INK4/CDKN2 may play a significant role in progression of leptomeningeal melanocytic neoplasms. We also reviewed previously reported cases of leptomeningeal neoplasms associated with NCM and discussed the relationship between the biological behavior and proliferative activity of such lesions.
Primary melanocytic neoplasms of the leptomeninges are rare, but often develop in patients with neurocutaneous melanosis (NCM). NCM is characterized by the excessive proliferation of melanocytes in the leptomeninges and skin. Embryologically, neural crest-derived precursor cells differentiate into a number of cell types including leptomeningeal cells, glial cells, adrenal medullary cells, and melanocytes. NCM is considered to be caused by an embryological error in the development of the neuroectoderm, resulting in a form of congenital dysplasia involving the skin and leptomeningeal melanoblasts.1 Primary melanocytic neoplasms of the leptomeninges include melanocytoma, malignant melanoma (MM), melanocytosis, and melanomatosis.2 Melanocytoma and MM form masses, whereas melanocytosis and melanomatosis produce diffuse lesions. The diffuse lesions produced by melanocytosis lack histological signs of malignancy. On the other hand, those produced by melanomatosis exhibit the characteristic cytological features of malignancy. We experienced a rare autopsy case of leptomeningeal melanomatosis associated with NCM. Here, we describe this case and discuss the relationship between the biological behavior and pathological findings of such lesions.
Key words: melanoma, melanomatosis, neurocutaneous melanosis, p16, p53, proliferation
CLINICAL SUMMARY
Correspondence: Mai Matsumura, MD, Department of Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Email: [email protected] Received 29 August 2014. Accepted for publication 6 November 2014. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
A 44-year-old Japanese male suffered a seizure and a disturbance of consciousness due to hydrocephalus. He had multiple congenital cutaneous nevi with or without hair on his trunk and lower extremities (Fig. 1a). Although he had been healthy for most of his life, he had suffered from neck pain and memory loss for the past few years. Gadoliniumdiethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced magnetic resonance imaging detected diffuse linear highintensity lesions on the surface of his brain and spinal cord. A cytological examination of the patient’s cerebrospinal fluid,
Leptomeningeal melanomatosis with NCM
which was obtained via a lumbar tap, showed atypical cells containing cytoplasmic melanin granules (Fig. 1b). A brain biopsy detected MM cells, which had spread into the subarachnoid and Virchow–Robin spaces (Fig. 1c). Although it was not confirmed whether the lesion had invaded into the cerebral parenchyma, a histopathological diagnosis of leptomeningeal melanomatosis was made based on the presence of cytological atypia involving pleomorphic nuclei, frequent mitotic figures, and a high Ki67 labeling index (10.8%). Temozolomide chemotherapy and decompression for the hydrocephalus were performed; however, the chemotherapy had little effect on the disease progression, and the patient died of multiple brain hemorrhages 6 months later. Clinically, platelet count and clotting function were within normal limit, and bleeding tendency was not observed.
PATHOLOGICAL FINDINGS An autopsy was performed 5 h after the patient’s death. Multiple cutaneous pigmented nevi (diameter: 1–12 cm) with
Figure 1 (a) Photograph of the large pigmented nevi with hair on the patient’s lower extremities. (b) Cytology of the patient’s cerebrospinal fluid. Melanin-containing atypical cells were observed (arrow, Giemsa stain, ×400). (c) Histology of the brain biopsy sample. Malignant melanoma cells were found on the surface of the brain and in Virchow–Robin spaces (hematoxylin and eosin (HE) stain, × 40).
or without hair were observed on the patient’s trunk and lower extremities. Grossly, the brain was swollen and weighed 1580g (Fig. 2a). In addition, multiple hemorrhages were observed in the brain and subarachnoid space (Fig. 2b). A black lesion covered the surfaces of the brain and the spinal cord (Fig. 2c). Neither primary nor metastatic MM lesions were identified in other organs, including the skin. In the histological examinations, formalin-fixed paraffinembedded tissue sections were cut and stained with hematoxylin and eosin, and luxol fast blue–periodic acid Schiff (LFB–PAS) stain. In the immunohistochemical examinations, formalin-fixed paraffin-embedded tissue sections were incubated with primary antibodies against S-100 (polyclonal; Nichirei Bioscience, Tokyo, Japan), HMB45 (clone HMB4; DAKO, Ely, UK), Ki-67 (clone MIB-1; DAKO), p53 (clone DO-7, DAKO), and p16 (clone E61-14, Roche, Mannheim, Germany). Immunoreactivity was visualized with the Envision detection system (DAKO). The reactions were developed using commercially available AEC (3-amino-9-ethyl carbazole), and counterstaining was performed with hematoxylin.
a
a
Figure 2 (a) Gross appearance of the brain. The brain displayed marked swelling, and a black lesion covered its surface. (b) A cut section of the brain exhibited cerebral hemorrhage (arrow). (c) Cut sections from the thoracic to lumbar cord. The spinal cord was also covered with a thick black lesion. (d) Histology of the melanomatosis component. Melanin-containing tumor cells were observed on the brain surface and in Virchow–Robin spaces. The tumor cells had infiltrated into the cerebral parenchyma, and the border between the tumor and cerebral cortex was unclear (HE stain, × 100). (e) The tumor cells had also infiltrated into the spinal nerve roots (LFB–PAS stain, × 200). (f) Tumor cells had infiltrated into small blood vessels (HE stain, × 400).
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© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
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c
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The red of the positive AEC-staining cells could be distinguished from the brown of the melanin-containing tumor cells. The Ki-67 labeling index was calculated as the proportion of Ki-67-positive cells among up to three hundred cells. A histological examination of the patient’s leptomeningeal tissue detected diffusely distributed melanin-containing proliferating tumor cells. The tumor cells filled the subarachnoid spaces of the brain and spinal cord and in some regions they had infiltrated into the cerebral and spinal parenchyma via Virchow-Robin spaces (Fig. 2d,e). The maximum depth of the parenchymal invasion was limited to 1 mm. The bleeding in the brain and subarachnoid space was considered to have been caused by vascular invasion (Fig. 2f). At the invasive sites, the polygonal tumor cells showed marked cellular atypia involving pleomorphic nuclei and prominent nucleoli (Fig. 3a). More than 10 mitotic figures were observed in 10 high-power fields. The tumor cells were positively stained for S-100 and HMB45, and their Ki-67 labeling index was 8.7% (Fig. 4a). However, immunostaining of both p53 and p16 produced negative results (Fig. 4d,g). We diagnosed the invasive parts of the black lesion as leptomeningeal melanomatosis. Melanomatosis accounted for about 70% of the black lesion and was mainly distributed in the temporal lobe and spinal cord. In the parts of the lesion that did not exhibit invasion, the tumor cells showed milder cellular atypia together with mild nuclear pleomorphism (Fig. 3b). These cells contained almost no mitotic figures, and their Ki-67 labeling index was only 0.8% (Fig. 4b). Although p53 immunostaining produced a negative result, strong diffuse p16 positivity was detected (Fig. 4e,h). The tumor cells in the non-invasive regions did not display any malignant features, which was suggestive of leptomeningeal melanocytosis. Melanocytosis accounted for about 30% of the black lesion and was mainly distributed in the parietal lobe and cerebellum. The border between the melanomatosis and melanocytosis components was unclear, and a continuous transition between the different types of cellular atypia exhibited by these two components was observed. Furthermore, benign-looking spindle-shaped mature melanocytes were scattered on the arachnoid membrane around the black lesion (Fig. 3c). Mitotic figures were absent from the melanocytes, which exhibited a Ki-67 labeling index of 0% (Fig. 4c). p53 immunostaining produced a negative result, but strong diffuse p16 positivity was detected, which was indicative of leptomeningeal melanocyte hyperplasia (Fig. 4f,i). A histological examination of the skin lesions detected pigmented nevi of the intradermal type.
DISCUSSION NCM is a rare congenital syndrome in which benign or malignant melanocytic neoplasms of the leptomeninges are found
a
b
c
Figure 3 Histological findings of the (a) melanomatosis, (b) melanocytosis, and (c) melanocyte hyperplasia components (HE stain, × 400). (a) In the melanomatosis component, the tumor cells possessed a large amount of variably pigmented cytoplasm together with large and pleomorphic nucleoli and conspicuous nucleoli. (b) In the melanocytosis component, the tumor cells had smaller round nuclei and contained cytoplasmic melanin granules. (c) In the melanocyte hyperplasia component, spindle-shaped mature melanocytes without cellular atypia were sporadically distributed on the arachnoid membrane.
in the context of large and/or numerous congenital melanocytic nevi. NCM was first reported by Rokitansky in 1861.3 So far, at least 200 cases of NCM have been reported in the English literature, and about 70 cases have been reported in the Japanese literature since 1914. As for autopsy cases, only about 10 cases have been reported in the English literature. In 1972, Fox proposed clinical criteria
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Leptomeningeal melanomatosis with NCM
Figure 4 Immunohistochemical findings of the (a,d,g) melanomatosis, (b,e,h) melanocytosis, and (c,f,i) melanocyte hyperplasia components. The three components were subjected to immunohistochemical analyses of their (a–c) Ki-67 indices, (d–f) p53 and (g–i) p16 expression. Positive cells appear red signal as opposed to melanin brown granules. The Ki67 labeling indices of the melanomatosis, melanocytosis, and melanocyte hyperplasia components were (a) 8.7%, (b) 0.8%, and (c) 0%, respectively. (d–f) p53 was not detected in any of the three components. (g) p16 immunostaining produced a negative result in the melanomatosis component, but (h,i) detected strong diffuse p16 positivity (red-colored) in the melanocytosis and melanocyte hyperplasia components.
a
b
c
d
e
f
g
h
i
for diagnosing the condition.4 The definition of NCM was subsequently refined by Kadonaga and Frieden in 1991 to include:1 1 Large (>20 cm in largest diameter in adult cases) or multiple (three or more) congenital nevi in association with meningeal melanosis or melanoma. In infant cases, congenital nevi on the head that measure 9 cm in diameter and those on the body that measure 6 cm in diameter are considered to meet the criteria for NCM because the projected growth of a lesion’s surface area is assumed to be proportional to the normal skin growth of the body region it lies within. 2 No evidence of cutaneous melanoma except when the examined areas of meningeal lesions are histologically benign. 3 No evidence of meningeal melanoma except when the examined areas of cutaneous lesions are histologically benign. In general, primary melanocytic neoplasms of the leptomeninges are classified into two types, the mass-forming type, such as melanocytoma or MM, and the diffuse type, such as melanocytosis or melanomatosis. The incidence of melanocytoma is 1 per 10 million, and the incidence of MM is 1 per 20 million.5 Diffuse leptomeningeal melanocytic lesions are rarer than mass-forming lesions, although no data regarding their population-based incidence rates are available. The prognosis of diffuse melanocytic neoplasms is poor, even in the absence of histological malignancy,5 and about 50% of patients with
103
diffuse type lesions die within three years of the onset of neurological symptoms.1 NCM patients that display leptomeningeal involvement are at risk of developing MM or melanomatosis, which exhibit estimated prevalence rates of 40–60% among this group.1 As for the background changes that lead to melanomatosis, benign components like melanocytosis or melanocyte hyperplasia are commonly observed in cases of melanomatosis.6 In previous studies, the biological behavior of leptomeningeal melanocytic neoplasms associated with NCM was comprehensively assessed based on data regarding cellular atypia, mitosis, invasion, bleeding, and the Ki-67 labeling index; however, it is still difficult to distinguish between melanocytosis and melanomatosis.6–8 In previous studies of skin melanocytic tumors, the Ki-67 labeling index was reported to be less than 10% in benign tumors, to range from 2–85% (mean: 34%), and generally be above 50% in MM.9 On the other hand, the Ki-67 labeling index of leptomeningeal melanocytic tumors has been reported to range from 0 to 2% (mean: 0.5%) in mass-forming melanocytoma and from 2 to 15% (mean: 7.8%) in massforming MM.10 Moreover, intermediate-grade tumors were defined in the AFIP atlas of tumor pathology, and a Ki-67 labeling index of 1–4% was proposed as one of the criteria for identifying such lesions. However, only 10 cases of leptomeningeal melanocytic neoplasms associated with NCM, including the present one, have been reported in the literature, and previous case reports have not provided much detailed information about the histopathological features, proliferative activity, or prognosis of such lesions.6–8,11–16 The clinical and pathological
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
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M. Matsumura et al.
Table 1
Review of reported cases of leptomeningeal melanocytic neoplasms associated with neurocutaneous melanosis (NCM) Histopathological features
Cases Malignant tumor 1 [6]
Age Sex
Material
Location
Nuclear form
Bleeding Invasion
Ki67 labeling index
Histological diagnosis
Outcome
33
M
Autopsy Brain, spinal Pleomorphic
+
+
2 [11] 3 [7]
35 9
M F
Biopsy Brain Autopsy Brain
NA NA
NA +
2.54% Melanomatosis D[6M] (1.2–10.5%) 11% Melanomatosis D[31M] High Melanomatosis D[12M]
4 [12] 5 [13]
1 1
M F
Biopsy Surgery
NA NA
NA NA
≥30% ≥80%
44
M
Autopsy Brain, spinal Polygonal
+
+
8.70%
10 3 40 9
F M F F
Surgery Surgery Surgery Autopsy
− − NA −
− − NA −
0% Low
